Orally active azole derivatives

ABSTRACT

The present invention relates to new orally active azole derivatives with antifungal activity of formula I ##STR1## wherein: X is CH or N; Ar represents phenyl substituted with halogen and/or trifluoromethyl; Z is --C(=O)-- or --SO 2  --; R 1  is CN, CO 2  H, CO 2  R 7 , CONR 8  R 9  or CH 2  Y and then R 3  is hydrogen, or R 1  together with R 3  forms a ring of formula I&#39; ##STR2## wherein B is O, hydroxy or hydrogen; R 4  is C 1-4  alkyl; R 5 , R 6 , R 8  and R 9  are hydrogen or C 1-4  alkyl; Y is --OH, --OR 7 , --OC(=O)R 7 , --NR 8  R 9 , --NHC(=O)OR 7  ; R 7  is C 1  -C 4  -alkyl, phenyl-C 1  -C 4  -alkyl or optionally substituted phenyl; when Z is --C(=O)--, R 2  is optionally susbtituted phenyl, or naphtyl; when Z is --SO 2  --, R 2  is C 1-4  alkyl, phenyl-C 1-4  -alkyl or optionally susbtituted phenyl.

FIELD OF THE INVENTION

The present invention relates to a new series of azole derivatives ofgeneral formula I having a potent antifungal activity. The inventionalso relates to a process for their preparation, to the pharmaceuticalcompositions containing them and to their use for the treatment offungal diseases.

DESCRIPTION OF THE PRIOR ART

The compounds of the present invention are antifungal agents whosemechanism of action is based on the inhibition of the biosynthesis ofergosterol in fungi. Other antifungal agents having this type ofactivity are known in the medical practice and are currently used intherapy. Some of them are applied in the topical treatment of fungalinfections of the skin, vagina and nails, such as candidiasis,dermatophytosis and pityriasis. More recently discovered compounds areused orally in the treatment of systemic and organ mycoses, such assystemic candidiasis, aspergillosis, criptoccocal meningitis,coccidioidomycosis, paracoccidioidiomycosis, histoplasmosis,sporotrichosis, chromoblastomycosis and blastomycosis. These diseasesappear frequently in immunosupressed patients, such as AIDS and cancerpatients. Some other compounds related to the ones of the presentinvention are also used as agrochemicals to protect plants from avariety of fungi.

European patent application EP 332,387 describes, among others, certainantifungal compounds of general formula ##STR3## wherein: Ar is a phenylgroup optionally substituted by one or two halogen or trifluoromethylgroups; R₂ is C₁ -C₆ alkyl, haloalkyl, optionally substituted phenyl,naphtyl or an heterocycle; and R1 is H or C₁ -C₄ alkyl. These compoundsare useful for the treatment of fungal diseases in animals and plants.

In a study aimed at improving the activity of these compounds, we havefound that an increase in the lenght of the alkyl radical R₁ in acompound of the above formula (that is to say the change of methyl forethyl, propyl and butyl) translates into a progressive loss of in vivoactivity. But, surprisingly, the introduction of an heteroatom into thegroup R₁ leads to a recovery or even an improvement of the activity ofthe prior art compounds. The new compounds do not fall within the scopeof the above mentioned patent application. Thus, the present inventiondescribes new compounds structurally related to the above mentioned,where the nature of the substituent R₁ has been substantially modifiedso as to contain one or more heteroatoms.

DESCRIPTION OF THE INVENTION

The present invention relates to new compounds of general formula I asracemates, diastereomer mixtures or as homochiral compounds ##STR4##wherein

X is CH or N;

Ar represents phenyl or a phenyl ring substituted with one or morehalogen and/or trifluoromethyl groups;

Z is --C(=O)-- or --SO₂ --;

R₁ is CN, CO₂ H, CO₂ R₇, CONR₈ R₉ or CH₂ Y and then R₃ is hydrogen, orR₁ together with R₃ and the remainder or salt compound of Formula Iforms a six-membered ring of formula I forms a six-membered ring offormula I' ##STR5## wherein B is O, in which case the dotted linerepresents a covalent bond, or B is hydroxy, fluorine, hydrogen or1-H-1,2,4-triazol-1-yl, in which case the dotted line is absent;

Y is --OH, --OR₇, --OC(=O)R₇, --NR₈ R₉, --NHC(=O)OR₇,1-H-1,2,4-triazol-1-yl or 1H-imidazol-1-yl;

R₄ is C₁₋₄ alkyl;

R₅, R₆, R₈ and R₉ are independently hydrogen or C₁₋₄ alkyl;

R₇ is C₁ -C₄ -alkyl, phenyl-C₁ -C₄ -alkyl, phenyl or phenyl susbtitutedwith a group R₁₀ ;

when Z is --C(=O)--, R₂ is phenyl, phenyl substituted with one or moregroups R₁₀, or naphtyl;

when Z is --SO₂ --, R₂ is C₁₋₄ alkyl, phenyl-C₁₋₄ -alkyl, phenyl orphenyl substituted with one or more groups R_(10;)

R₁₀ represents C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C1-C4 alkoxy, C₁ -C₄haloalkoxy, halogen, nitro, cyano, hydroxy, benzyloxy, hydroxymethyl, agroup of formula --CH₂ --OCO--(C₁₋₄ alkyl), a group of formula--CO--(C₁₋₄ alkyl), a group of formula --COO--(C₁₋₄ alkyl), a groupformula --SO_(z) (C₁₋₄ alkyl) wherein z is 0, 1 or 2, amino, mono- ordialkylamino wherein alkyl means C₁ -C₄ alkyl; and

the salts and solvates thereof.

The invention also provides a pharmaceutical composition which comprisesan effective amount of a compound of formula I or a pharmaceuticallyacceptable salt or solvate thereof in admixture with a pharmaceuticallyacceptable excipient.

The present invention further provides the use of a compound of formulaI or a pharmaceutically acceptable salt or solvate thereof in thetreatment or prophylaxis of fungal infections. Accordingly, theinvention provides a method for treating or preventing fungal infectionsin an animal, which may be a human being, which comprises administeringto an animal in need thereof an effective amount of a compound offormula I or a pharmaceutically acceptable salt or solvate thereof.

The compounds of the present invention possess antifungal propertieswhich are useful in combatting a wide variety of plant fungal diseases.The invention thus provides the use of a compound of formula I or a saltor solvate thereof for the treatment or prophylaxis of fungal infectionsin plants. Accordingly, the invention provides a method of combattingfungal diseases in a plant which comprises administering to the plant aneffective amount of a compound of formula I or a salt or solvatethereof. The invention still further provides an agrochemicalcomposition comprising an effective amount of a compound of formula I ora salt or solvate thereof in admixture with an agronomically acceptableexcipient.

The invention also provides a process for preparing a compound offormula I, which process comprises

(a) reacting a compound of formula II ##STR6## wherein X, Ar, R₁, R₄, R₅and R₆ have the previously defined meaning, with an acid of formula R₂COOH or a reactive derivative thereof, such as the acid chloride, orwith a sulfonyl chloride of formula R₂ SO₂ Cl under standardexperimental conditions, and optionally interconverting the group R₁ ofa compound of formula I into other groups R1 by standard chemicalreactions; or

(b) oxidating a compound of formula I wherein R₁ is CH₂ OH to thealdehyde to give a lactol of formula I', wherein B is hydroxy and thedotted line is absent, and optionally transforming this hydroxy groupinto other groups by standard chemical reactions; or

(c) reacting a compound of formula I wherein R₁ is CO₂ H with anappropriate dehydrating agent to give a lactone of formula I' wherein Bis O and the dotted line represents a covalent bond; or

(d) subjecting a compound of formula I wherein R₁ is CH₂ OH to standardMitsunobu conditions to give a compound of formula I', wherein B ishydrogen and the dotted line is absent.

Also included in the present invention are novel intermediates offormula II ##STR7## wherein X, Ar, R₁, R₄, R₅ and R₆ are as defined forcompounds of formula I.

In the above definitions, a C₁₋₄ alkyl group means a linear or branchedalkyl chain containing from 1 to 4 carbon atoms. It includes methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

A C₁₋₄ haloalkyl group means a group resulting from the substitution ofone or more hydrogen atoms of a C₁₋₄ alkyl group by one or more halogenatoms (i.e. fluorine, chlorine, bromine or iodine), which can be thesame or different. Examples include trifluoromethyl, fluoromethyl,chloroethyl, fluoroethyl, iodoethyl, pentafluoroethyl, fluoropropyl,chloropropyl, 2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrafluoropropyl,heptafluoropropyl, etc.

A C₁₋₄ alkoxy group means a group derived from the union of a C₁₋₄ alkylgroup to an oxygen atom of an ether functional group. Examples includemethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy andtert-butoxy.

A C₁₋₄ haloalkoxy group means a group resulting from the substitution ofone or more hydrogen atoms of a C₁₋₄ alkoxy group like the abovementioned by one or more halogen atoms, which can be the same ordifferent. Examples include trifluoromethoxy, fluoromethoxy,chloroethoxy, fluoroethoxy, iodoethoxy, 2,2,2-trifluoroethoxy,pentafluoroethoxy, fluoropropoxy, chloropropoxy,2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy,heptafluoropropoxy, etc.

In the compounds of the present invention, X represents a nitrogen atomor a CH group, but preferably is a nitrogen atom.

In the compounds where R₂ represents a substituted phenyl ring, saidsubstituent(s) can be C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxy, C₁-C₄ haloalkoxy, halogen, nitro, cyano, hydroxy, benzyloxy,hydroxymethyl, a group of formula --CH₂ --OCO--(C₁₋₄ alkyl), a group offormula --CO--(C₁₋₄ alkyl), a group of formula --COO--(C₁₋₄ alkyl), agroup formula --SO_(z) (C₁₋₄ alkyl) wherein z is 0, 1 or 2, amino, mono-or dialkylamino wherein alkyl means C₁ -C₄ alkyl. When there are morethan one substituent, they can be the same or different. When thesubstituent is an halogen atom, this can be fluorine, chlorine, bromineor iodine. Examples of substituted phenyl rings include 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,pentafluorophenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl,4-(trichloromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl,2-fluoro-4 -(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl,4-(difluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl,4-(2,2,2-trifluoroethoxy)phenyl, 4-(2,2,3,3-tetrafluoropropoxy)phenyl,3-nitrophenyl, 4-nitrophenyl, 2-fluoro-4-nitrophenyl, 3-cyanophenyl,4-cyanophenyl, 2-chloro-4-cyanophenyl, 4-(methoxycarbonyl)phenyl,2-fluoro-4-(ethoxycarbonyl)phenyl, 4-(methylthio)phenyl,4-(methylsulfinyl)phenyl and 4-(methylsulfonyl)phenyl, of which4-chlorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl,2-fluoro-4-(trifluoromethyl)phenyl, 4-cyanophenyl, 4-nitrophenyl,4-(trifluoromethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl and4-(2,2,3,3-tetrafluoropropoxy)phenyl are preferred, and 4-chlorophenyl,4-fluorophenyl, 4-(trifluoromethyl)phenyl,2-fluoro-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-(2,2,2-trifluoroethoxy)phenyl and 4-(2,2,3,3-tetrafluoropropoxy)phenylare more preferred.

In the compounds of the present invention, R₂ can have all the abovementioned meanings, but preferably is phenyl substituted with one ormore groups R₁₀.

In the compounds of the present invention Ar represents a phenyl groupor a phenyl group substituted with one or more halogen and/ortrifluoromethyl groups. The halogen atoms may be fluorine, chlorine,bromine or iodine atoms, of which fluorine and chlorine atoms arepreferred. There may be one or more such substituents on the phenylgroup, and where there are more than one, these may be the same ordifferent. The substituents may be on any available position of thephenyl group, but they are preferably on the 2- and/or 4-positions.Examples of the Ar group include the phenyl group itself,4-(trifluoromethyl)phenyl, 4-fluorophenyl, 2-chloro-4-fluorophenyl,4-chloro-2-fluorophenyl, 4-bromophenyl, 2-fluoro-4-iodophenyl,2,4-dichlorophenyl, 2,4-difluorophenyl, 4-chlorophenyl and2-fluoro-4-(trifluoromethyl)phenyl, of which 4-fluorophenyl,2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,4-(trifluoromethyl)phenyl and 4-chlorophenyl are preferred, and2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl and4-chlorophenyl are more preferred.

In a compound of formula I, Z represents --C(=O)-- or --SO₂ --, butpreferably represents --C(=O)--.

In a compound of formula I, R₄ is C₁₋₄ alkyl, but preferably is methyl.

In a compound of formula I, R₅ is hydrogen or C₁₋₄ alkyl, but preferablyis hydrogen.

In a compound of formula I, R₆ is hydrogen or C₁₋₄ alkyl, but preferablyis hydrogen or methyl.

In those compounds where R₁ together with R₃ and the remainder of saltcompound or Formula I may form a six-membered ring of formula I'##STR8## wherein B is O, in which case the dotted line represents acovalent bond, or B is hydroxy, fluorine, hydrogen or1-H-1,2,4-triazol-1-yl, in which case the dotted line is absent, thosein which B represents O, hydroxy or hydrogen are preferred.

Preferred embodiments of the present invention are those compounds offormula I wherein:

X is N;

R₂ is phenyl or phenyl substituted with one or more groups R₁₀ ; and

Ar, Z, R₁, R₃, R₄, R₅, R₆ and R₁₀ have the previously defined meaning.

More preferred embodiments of the present invention are those compoundsof formula I wherein:

X is N;

Z is --C(=O)--;

R₂ is phenyl or phenyl substituted with one or more groups R₁₀ ; and

Ar, R₁, R₃, R₄, R₅, R₆ and R₁₀ have the previously defined meaning.

Still more preferred embodiments of the present invention are thosecompounds of formula I wherein:

X is N;

Z is --C(=O)--;

R₂ is phenyl or phenyl substituted with one or more groups R₁₀ ;

R₄ is methyl;

R₅ is hydrogen or methyl; and

Ar, R₁, R₃, R₆ and R₁₀ have the previously defined meaning.

Particularly preferred embodiments of the present invention are thefollowing groups of compounds:

I) Those compounds of formula I where:

X is N;

Z is --C(=O)--;

R₂ is 4-chlorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl,2-fluoro-4-(trifluoromethyl)phenyl, 4-cyanophenyl, 4-nitrophenyl,4-(trifluoromethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl or4-(2,2,3,3-tetrafluoropropoxy)phenyl;

R₄ is methyl;

R₅ is hydrogen;

R₁ is CN, CH₂ NH₂ or CH₂ OH;

R₃ is hydrogen;

Ar is 4-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; and

R₆ is hydrogen.

II) Those compounds of formula I' where:

X is N;

Z is --C(=O)--;

R₂ is 4-chlorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl,2-fluoro-4-(trifluoromethyl)phenyl, 4-cyanophenyl, 4-nitrophenyl,4-(trifluoromethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl or4-(2,2,3,3-tetrafluoropropoxy)phenyl;

R₄ is methyl;

R₅ is hydrogen;

B is O in which case the dotted line represents a covalent bond, or B ishydroxy, in which case the dotted line is absent;

Ar is 4-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; and

R₆ is hydrogen.

Most preferred embodiments of the present invention are the followinggroups of compounds:

I) Those compound of formula I where:

X is N;

Z is --C(=O)--;

R₂ is 4-chlorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl,2-fluoro-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-(2,2,2-trifluoroethoxy)phenyl or 4-(2,2,3,3-tetrafluoropropoxy)phenyl;

R₄ is methyl;

R₅ is hydrogen;

R₁ is CH₂ OH;

R₃ is hydrogen;

Ar is 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenylor 4-chlorophenyl; and

R₆ is hydrogen.

II) Those compounds of formula I' where:

X is N;

Z is --C(=O)--;

R₂ is 4-chlorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl,2-fluoro-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-(2,2,2-trifluoroethoxy)phenyl or 4-(2,2,3,3-tetrafluoropropoxy)phenyl;

R₄ is methyl;

R₅ is hydrogen;

B is O in which case the dotted line represents a covalent bond;

Ar is 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenylor 4-chlorophenyl; and

R₆ is hydrogen.

lII) Those compounds of formula I' where:

X is N;

Z is --C(=O)--;

R₂ is 4-chlorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl,2-fluoro-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-(2,2,2-trifluoroethoxy)phenyl or 4-(2,2,3,3-tetrafluoropropoxy)phenyl;

R₄ is methyl;

R₅ is hydrogen;

B is hydroxy, in which case the dotted line is absent;

Ar is 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenylor 4-chlorophenyl; and

R₆ is hydrogen.

The compounds of formula I contain one or more basic nitrogen atoms and,consequently, they can form salts with acids, which are also included inthe present invention. There is no limitation on the nature of thesesalts, provided that, when used for therapeutic purposes, they arepharmaceutically acceptable, which, as is well-known in the art, meansthat they do not have reduced activity (or unacceptable reducedactivity) or increased toxicity (or unacceptable increased toxicity)compared with the free compounds. Examples of these salts include: saltswith an inorganic acid such as hydrochloric acid, hydrobromic acid,hydriodic acid, nitric acid, perchloric acid, sulfuric acid orphosphoric acid; and salts with an organic acid, such as methanesulfonicacid, trifluoromethanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acidor maleic acid. The salts are prepared by reacting the free base with asufficient amount of the desired acid to produce a salt in theconventional manner. Free bases and their salts differ in certainphysical properties, such as solubility, but they are equivalent for thepurposes of the invention.

The compounds of the present invention can exist in unsolvated as wellas solvated forms, including hydrated forms. In general, the solvatedforms, with pharmaceutically acceptable solvents such as water, ethanoland the like, are equivalent to the unsolvated forms for the purposes ofthe invention.

The compounds of the present invention can exist as differentdiastereoisomers and/or optical isomers because of the existence ofasymmetric carbons in their skeleton. These stereoisomers and themixtures thereof are all included in the present invention. Inparticular, when R₄ is methyl and R₅ is hydrogen, the compounds whereinthe carbon to which the Ar group is bonded and the carbon to which R₄ isbonded bear the (R*,R*) relative stereochemistry are preferable, and thehomochiral compounds wherein the carbon to which the Ar group is bondedand the carbon to which R₄ is bonded are both R-configurated are morepreferable.

Diastereoisomers can be separated by conventional techniques such aschromatography or fractional crystallization. The optical isomers can beresolved using any of the conventional techniques of optical resolutionto give optically pure isomers. Such a resolution can be performed inany chiral synthetic intermediate as well as in the products of generalformula I. The optically pure isomers can also be individually obtainedusing enantiospecific synthesis, as explained in more detail below. Asstated above, the present invention covers the individual isomers aswell as their mixtures (e.g. racemic mixtures), whether as obtained bysynthesis or by physically mixing them up.

The present invention also provides a process for the preparation of thecompounds of formula I. The precise method used for the preparation of agiven compound will vary depending on its chemical structure. Thegeneral method for their preparation is illustrated in Schemes 1, 2 and3. ##STR9##

Wherein X, Ar, Z, R₁, R₄, R₅ and R₆ have the previously defined meaning.

As shown in Scheme 1, compounds of formula I" (i.e. compounds of formulaI, wherein R₃ represents hydrogen) are prepared from amines of formulaII by reaction with an acid chloride of formula R₂ COCl or anotherreactive derivative of R₂ COOH or a sulfonyl chloride of formula R₂ SO₂Cl in the presence of a proton scavenger, such as triethylamine orpyridine, in a suitable solvent, such as chloroform or dichloromethane,or using the base as solvent. The reaction is carried out at atemperature between -10° C. and that of the boiling point of thesolvent, preferably between 0° and 25° C. The time required for thereaction may vary widely, depending on many factors, notably thereaction temperature and the nature of the reagents, but in general aperiod of time from 30 min to 24 h will usually suffice. If required,the compounds thus obtained can be purified by conventional methods suchas flash chromatography or recrystallization. As an alternative to theacid chloride, the anhydride can be employed. Alternatively, compoundsof formula I" wherein Z=--C(=O)-- may be prepared by a coupling reactionbetween amines of formula II and an acid of formula R₂ COOH. Thisprocess can be carried out using any conventional reaction of amide bondformation, such as reacting an amine with an acid in the presence of anappropriate condensing agent such as dicyclohexylcarbodiimide (DCC)alone or in combination with 1-hydroxybenzotriazole.

Acids of formula R₂ COOH and the reactive derivatives thereof (i.e. acidchloride or anhydride) as well as sulfonyl chlorides of formula R₂ SO₂Cl are either commercially available, or widely described in theliterature or can be prepared by methods similar to those described,starting from commercially available products.

Furthermore, the group R₁ in a compound of formula I thus obtained maybe transformed into other groups R₁ by standard chemical reactions,which are well known to those skilled in the art.

For example, if R₁ is a benzyl ether, this product can be converted tothe alcohol (R₁ =CH₂ OH) by hydrogenation in the presence of a catalyst,such as palladium or platinum, in a suitable solvent such as an alcohol,for example ethanol, at a hydrogen pressure between 1 and 5 atm. Thereaction can take place over a wide range of temperatures and theprecise temperature is not critical to the invention. In general, wefind it convenient to carry out the reaction at about room temperature.

The resulting alcohol can be transformed into other functionalities wellknown in organic chemistry, such as an ester, using standard reactions.

Furthermore, a group R₁ of formula CH₂ NHC(=O)OR₇ may be transformedinto an amine group following standard conditions; when it is a CH₂NHBOC group, this process can be carried out for example by treatmentwith trifluoroacetic acid in dioxane or with hydrochloric acid inmethanol.

When R₁ =CO₂ R₇, this product can be hydrolized to the acid (R₁ =CO₂ H)following conventional procedures. If R₁ is a benzyl ester, this processcan be carried out by hydrogenation under the same experimentalconditions mentioned above for benzyl ethers.

Compounds as seen in formula I wherein R¹ together with R³ form a ringof formula I', wherein B is hydrogen and the dotted line is absent, canbe obtained directly from the corresponding alcohol derivatives offormula I (i.e. compounds of formula I wherein R₁ =CH₂ OH) understandard Mitsunobu conditions (i.e. diethylazadicarboxylate,triphenylphosphine).

Compounds of formula I wherein R¹ together with R³ form a ring offormula I', wherein B is hydroxy, are prepared from the correspondingalcohol derivatives of formula I (i.e. compounds of formula I wherein R₁=CH₂ OH), as shown in Scheme 2: ##STR10##

This transformation (Scheme 2) involves the oxidation of a primaryalcohol to an aldehyde, which spontaneously forms a cyclic acetal(lactol) with the tertiary hydroxyl group. This can be achieved by anyknown oxidation conditions currently used for the transformation ofalcohols into aldehydes. One set of such conditions are the so-calledMoffat oxidations which involve the use of activated DMSO and a base.Thus, we have found that treatment of DMSO with an activating agent,such as oxalyl chloride or trifluoroacetic anhydride, in the presence ofa suitable solvent, such as dichloromethane or chloroform, followed byaddition of the alcohol at low temperatures, and finally treatment witha base, such as triethylamine, affords the lactol in good yields.Alternatively, the oxidation of the primary alcohol to the aldehydestage can be achieved by other known methods, such as the Sharpless'ruthenium oxidation which involves the use of N-methylmorpholine N-oxideand a catalytic amount of tris-triphenylphosphine ruthenium (II)dichloride in a polar solvent, such as acetone.

The hydroxy group in a compound of formula I' thus obtained may betransformed into other groups following standard procedures. Forexample, it may be transformed into a fluorine atom (e.g. withdiethylaminosulfur trifluoride in dichloromethane, at -10° C.) or into a1-H-1,2,4-triazol-1-yl group (e.g. withdiethylazadicarboxylate/1,2,4-triazole/triphenylphosphine intetrahydrofuran, at 0° C.-room temperature).

Compounds of formula I wherein R¹ together with R³ and the remainder ofsaid compound of Formula I form a ring of formula I', wherein B is O andthe dotted line represents a covalent bond, are prepared from thecorresponding acids of formula I (i.e. compounds of formula I wherein R₁=CO₂ H) using an appropriate dehydrating agent, as formula I wherein R₁=CO₂ H) using an appropriate dehydrating agent, as shown in Scheme 3:##STR11##

The transformation can be achieved by using DCC in the presence of asuitable solvent, such as dimethylformamide, at a wide range oftemperatures and reaction conditions. Filtration of the precipitatedurea formed during the reaction affords the lactone in very high yields.Alternatively, the transformation can be performed under otherdehydrating conditions, all of them involving the in situ formation ofan active acid derivative. Suitable reagents for this transformation aretrifluoroacetic anhydride, oxalyl chloride or thionyl chloride, amongothers. The reaction can be done at a wide range of conditions but wehave found that heating a pyridine solution containing the hydroxyacidand trifluoroacetic anhydride gives excellent yields of the desiredlactone.

In some cases, these compounds may also be obtained from compounds offormula I wherein R₁ =CH₂ OH by oxidation of the primary alcohol to theacid to give a lactone of formula I'. This process can be carried out bytreatment of the alcohol, for example, with Fetizon's reagent (Ag₂ CO₃)suspended in celite in a suitable solvent, such as benzene, at thetemperature of the boiling point of the solvent.

Compounds of formula I wherein R₁ represents CONR₈ R₉ can be obtained bytreatment of the corresponding lactone with ammonium hydroxide or anamine. Selective reduction of the amides thus obtained using for exampleLiBH₄ in diglyme affords the compounds of formula I wherein Y=NR₈ R₉.

Starting compounds of formula II are prepared from amines of formula IIIas shown in Scheme 4 below: ##STR12## Wherein R₁ * represents R₁ or agroup convertible thereto.

Amines of formula II may be obtained by treatment of an amine of formulaIII with an alkylating agent of formula WCHR₁ R₆ (wherein W is a leavinggroup such as chloro, bromo, mesyloxy or p-toluenesulfonyloxy, and R₁and R₆ have the previously defined meaning) (step A) in the presence ofan amine, such as triethylamine or pyridine, and in a solvent. Suitablesolvents are preferentially those with high polarity such astetrahydrofuran, acetonitrile or dioxane. The reaction is carried out ata temperature between room temperature and that of the boiling point ofthe solvent; the reaction time will depend mainly on the nature of thealkylating agent and the temperature, but a period of time between 1 hand 72 h will usually suffice.

Alternatively, amines of formula II wherein R₆ =H may also be obtainedby the following sequence: reaction of an amine of formula III (step B)with a compound of formula R₁ *CHO, wherein R₁ * has the previouslydefined meaning, in a suitable solvent such as an aromatic hydrocarbon,for example benzene or toluene, at a temperature between 50° C. and thatof the boiling point of the solvent, to give the correspondingoxazolidine of formula IV (generally as a mixture of stereoisomers); ifnecessary, transformation of R₁ * to a group R₁ following conventionalprocedures; and finally, reduction of IV (step C) with an excess oflithium aluminium hydride (LiAlH₄) in an inert solvent. Examples ofsuitable solvents include: ethers, such as diethyl ether,tetrahydrofuran or dioxane. The reaction is carried out at a temperaturebetween -20° C. and that of the boiling point of the solvent.

Furthermore, it is also possible to transform the group R₁ of a compoundof formula II into other groups R₁ by standard chemical reactions, as itwill become apparent to a person skilled in the art.

Compounds of formulae WCHR₁ R₆ and R₁ *CHO are either commerciallyavailable, or widely described in the literature or can be prepared bymethods similar to those described, starting from commercially availableproducts.

Amines of formula III can be prepared according to the proceduredescribed in patent application EP 332387.

The present invention also provides a method for preparing the opticallypure isomers of the compounds of formula I. They may be obtainedfollowing the same general procedure explained above for the preparationof compounds of formula I, but starting from the optically pure aminesof formula III.

Optically pure amines of formula III wherein R₅ =H having the (R,R)absolute stereochemistry may be prepared according to the proceduredescribed in EP 332387. However, the synthesis thereby reported is longand tedious, it requires the use of expensive reactants and in somesteps racemization is somewhat unpredictable. We therefore undertook astudy aimed at obtaining the homochiral products of formula III (i.e.the precursors of the homochiral compounds of formula I of the presentinvention) in a more practical manner. Thus, the present inventionfurther provides a new, highly convergent synthesis of amines of formulaIII consisting in an enantioselective process using the Evans' chiraloxazolidinones. The process summarized in Scheme 5. ##STR13## Wherein:

D represents phenyl, benzyl, isopropyl or tert-butyl;

E represents hydrogen, or when D is phenyl, E can also be methyl; and

X, Ar and R₄ have the previously defined meaning. According to Scheme 5,the two chiral centers are introduced stereoselectively in one singlestep (Step A) in an aldol condensation using an (S)-type Evans'oxazolidinone of formula V, i.e.(4S)-4-benzyl-3-propionyl-2-oxazolidinone,(4S)-4-isopropyl-3-propionyl-2-oxazolidinone,(4S)-4-phenyl-3-propionyl-2-oxazolidinone,(4S,5R)-3-propionyl-4-methyl-5-phenyl-2-oxazolidinone or the like, and ahaloacetophenone of formula ArCOCH₂ W, where W is a leaving group suchas chloro, bromo, mesyloxy or p-toluenesulfonyloxy, but preferably is abromine atom, and Ar is as defined above. The enolizing agent can be anycommonly used enolizing agent such as lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, sodium hydride, sodiumbis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide, butpreferably is sodium bis(trimethylsilyl)amide. The reaction can beperformed under a great variety of conditions and reagent proportions.For example, we have found that enolization with sodiumbis(trimethylsilyl)amide and condensation with 1.2 equivalents of theacetophenone at -78° C., using tetrahydrofuran as the solvent, gives anacceptable yield of the (2R,3R)-epoxide VI with good stereoselection.The only other epoxide formed during the reaction has an anti relativestereochemistry and, therefore, can be removed by recrystallization at alater stage. The desired compound can be purified by standard methodssuch as column chromatography, however we have found that the crudereaction mixture can be used in the next step as obtained. In a secondstep (Step B) the chiral auxiliary is removed under the reportedstandard conditions for this kind of auxiliaries (LiOH, H₂ O₂, THF, H₂O) (Tetrahedron Lett., 1987, 49, 6141-6144) to give the(2R,3R)-epoxyacid VII and the chiral auxiliary that can be recovered forfurther use. In a third step (Step C) the (2R,3R)-epoxyacid VII isconverted to the (2R,3R)-azoloacid VIII. This reaction is performedusing the azole (triazole or imidazole) and a base such as potassiumcarbonate, sodium hydride or potassium t-butoxide, preferably sodiumhydride, in a polar solvent, such as tetrahydrofuran ordimethylformamide, preferably dimethylformamide, at a temperature thatcan range from room temperature to the boiling point of tetrahydrofuranor to 120° C. if dimethylformamide is used. The (2R,3R)-azoloacid VIIIcan be purified by recrystallization at this step and, in this way,remove the traces of the anti isomers still present in the mixture. Thefinal step (step D) implies the conversion of the carboxyl group of acompound of formula VIII into an amine, with retention of configuration.We have found that this transformation is succesfully attained under theCurtius conditions, where an acylazide intermediate is rearranged to anisocyanate which is, in turn, internally captured by the hydroxyl of the3-position to afford an intermediate 2-oxazolidinone, which is directlyhydrolized to the amine of formula III. We have found that treating thecompound of formula VIII with diphenylphosphorylazide or alternatively,forming first the acid chloride of VIII in a manner being known per seand then treating this with sodium azide, to give an acylazideintermediate, and then heating this acylazide in the presence of a basesuch as triethylamine in a solvent such as benzene or tert-butanol,preferably the latter, at a temperature between room temperature andthat of the boiling point of the solvent, followed by alkalinehydrolysis of the resulting intermediate oxazolidinone under a varietyof alkaline conditions (as for example KOH in MeOH:H₂ O, reflux) affordsamine III with an optical yield identical to that reported in theliterature (Chem. Pharm. Bull., 1991, 39, 2581-2589). Having thehomochiral compound of formula III in hand, the homochiral compounds offormula I are prepared following the general procedure described above.

Optically active compounds of formulae VI, VII and VIII, which areuseful as intermediates for the preparation of a compound of formula I,are novel and are also included in the present invention.

According to the activity of the compounds disclosed, the presentinvention further provides compositions that contain a compound of thepresent invention, together with an excipient and optionally otherauxiliary agents, if necessary. The compounds of the present inventioncan be administered in different pharmaceutical preparations, theprecise nature of which will depend, as it is well known, upon thechosen route of administration and the nature of the pathology to betreated.

Thus, solid compositions according to the present invention for oraladministration include compressed tablets, dispersible powders, granulesand capsules. In tablets, one or more of the active component(s) isadmixed with at least one inert diluent such as lactose, starch,mannitol, microcrystalline cellulose or calcium phosphate; granulatingand disintegrating agents for example corn starch, gelatine,microcrystalline cellulose or polyvinylpyrrolidone; and lubricatingagents for example magnesium stearate, stearic acid or talc. The tabletsmay be coated by known techniques to delay disintegration and absorptionin the gastrointestinal tract and, thereby, provide a sustained actionover a longer period. Gastric film-coated or enteric film-coated tabletscan be made with sugar, gelatin, hydroxypropylcellulose, or acrylicresins. Tablets with a sustained action may also be obtained using anexcipient which provides regressive osmosis, such as the galacturonicacid polymers. Formulations for oral use may also be presented as hardcapsules of absorbable material, such as gelatin, wherein the activeingredient is mixed with an inert solid diluent and lubricating agents,or pasty materials, such as ethoxylated saturated glycerides. Softgelatin capsules are possible wherein the active ingredient is mixedwith water or an oil medium, for example peanut oil, liquid paraffin orolive oil.

Dispersible powders and granules suitable for preparation of asuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, a suspending agent, suchas sodium carboxymethylcellulose, sodium alginate, polyvinylpirrolidone,gum tragacanth, xantham gum, gum acacia, and one or more preservatives,such as methyl or n-propyl-p-hydroxybenzoate. Additional excipients, forexample sweetening, flavoring and coloring agents may also be present.

Liquid compositions for oral administration include emulsions,solutions, suspensions, syrups and elixirs containing commonly usedinert diluents, such as distilled water, ethanol, sorbitol, glycerol, orpropylene glycol. Such compositions may also comprise adjuvants such aswetting agents, suspending agents, sweetening, flavoring, perfuming,preserving agents and buffers.

Other compositions for oral administration include spray compositions,which may be prepared by known methods and which comprise one or moreactive compound(s). The spray compositions will contain a suitablepropellent.

Preparations for injection according to the present invention forparenteral administration include sterile aqueous or non-aqueoussolutions, suspensions or emulsions, in a non-toxicparentally-acceptable diluent or solvent. Solubility of the compoundscan be enhanced by the addition of cyclodextrins, such ashydroxypropyl-β-cyclodextrin. Examples of aqueous solvents or suspendingmedia are distilled water for injection, the Ringer's solution, andisotonic sodium chloride solution. Examples of non-aqueous solvents orsuspending media are propylene glycol, polyethylene glycol,dimethylacetamide, polyethylene glycol PEG 400, methyliden, vegetableoils such as olive oil, or alcohols such as ethanol. These compositionsmay also include adjuvants such as wetting, preserving, emulsifying anddispersing agents. They may be sterilized by one of the known methods ormanufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use. When all of the components are sterile, theinjectables will maintain the sterility if they are manufactured insterile environment.

Preparations for vaginal administration according to the presentinvention include tablets, capsules, softgels, moulded pessaries,creams, foams and vaginal douches. Vaginal tablets provide the activecomponent in admixture with lactose, microcrystalline cellulose,pregelatinized starch, polividone and magnesium stearate as typicalexcipients. Soft gelatin capsules (softgels) can be made dispersing theactive ingredient in an oily medium, for example liquid paraffin,dimethylpolysiloxane 1000 or hydrogenated soybean oil. Moulded pessariesprovide the active ingredient in admixture with a suitable synthetic orsemisynthetic base (such as Suppocire® or Novata® types). Low viscositysaturated C₈ to C₁₂ fatty acid glycerides and colloidal silice are alsoadded to improve incorporation and to prevent sedimentation of theactive ingredient. Vaginal creams can be prepared as emulsions, withsufficient viscosity to retain their integrity and adhere to the vaginalcavity. Neutral fats, fatty acids, waxes, mineral oils and fatty acidesters can be used as the oily phase. Water, glycerine, sorbitolsolution and polyethylene glycol are suitable excipients for the aqueousphase. Non-ionic emulsifying agents like polyethylene glycol ethers mayalso be used, and such compositions may also contain preserving,buffering and stiffening agents. Foaming systems can be made using afoamer (dispenser) that is able to transform a solution into a foam.Such systems may include cosolvents, buffers, preservatives, foamstabilizers and perfumes in an aqueous vehicle. Vaginal douches maycontain cosolvents, preservatives, buffers and perfuming agents in asurfactant rich aqueous solution.

A compound of the invention may also administered in the form ofsuppositories for rectal administration of the drug, or as creams,ointments, pastes, lotions, gels, sprays, foams, aerosols, solutions,suspensions or powders for topical use. Such compositions are preparedfollowing conventional procedures well known to those skilled in theart.

A compound of the invention may also be administered as a hair or bodyshampoo. These formulations may be prepared using suitable ionic and/oramphoteric surface-active agents such as sodium laureth sulfate,triethanolamine laureth sulfate, cocoamidopropyl betaine; thickeningagents for example cocamide DEA, carbomer, sodium chloride andpolyethylene glycol 6000 distearate; and optionally, emolient andsuperfatting agents, buffers, and preserving and perfuming agents.

The dosage and frequency of dose may vary depending upon the nature ofthe fungal disease, symptoms, age and body weight of the patient, aswell as upon the route of administration. Thus, for oral and parenteraladministration to human patients the daily dose will be from 1 to 1000mg for an adult, preferably a dosage of from 5 to 500 mg, which may beadministered either as a single dose or as divided doses. For topicaladministration, a cream or ointment containing 1-10% of a compound offormula I will be applied to the skin from one to three times daily.

Following are some representative preparations for tablets, capsules,aerosols and injectables. They can be prepared following standardprocedures and they are useful in the treatment of fungal diseases.

    ______________________________________                                        Tablets                                                                       Compound of formula I                                                                          100           mg                                             Dibasic calcium phosphate                                                                      125           mg                                             Sodium starch glycolate                                                                        10            mg                                             Talc             12.5          mg                                             Magnesium        2.5           mg                                                              250.0         mg                                             Hard gelatin capsules                                                         Compound of formula I                                                                          100           mg                                             Lactose          197           mg                                             Magnesium stearate                                                                             3             mg                                                              300           mg                                             Aerosol                                                                       Compound of formula I                                                                          4             g                                              Flavouring agent 0.2           g                                              Propylene glycol to                                                                            100           ml                                             Suitable propellent to                                                                         1             unit                                           Injectable preparation                                                        Compound of formula I                                                                          100           mg                                             Benzylic alcohol 0.05          ml                                             Propylene glycol 1             ml                                             Water to         5             ml                                             ______________________________________                                    

The following examples illustrate, but do not limit, the scope of thepresent invention:

REFERENCE EXAMPLE 1 (4R *,5R *)-2-Benzyloxymethyl-4-methyl-5-[(1-H-1,2,4-triazol-1-1-yl)methyl]-5-(2,4-difluorophenyl) oxazolidine ##STR14##

A solution containing(2R*,3R*)-3-amino-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-2-butanol(3.87 g, 14.42 mmol) (obtained according to patent EP 332387) andbenzyloxyacetaldehyde (2.17 g, 14.42 mmol) (obtained by NaIO₄ cleavageof DL-3-benzyloxy-1,2-propanediol) in benzene (40 mL) was heated atreflux for 4 h. The mixture was concentrated to afford the desiredproduct (6.01 g) as an oil. This product was directly used in the nextstep without further purification.

REFERENCE EXAMPLE 2(2R*,3R*)-3-[(2-Benzyloxyethyl)amino]-2-[2,4-difluorophenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR15##

To a cooled solution (0° C.) of the oxazolidine obtained in referenceexample 1 (6 g) in THF (40 mL) was added lithium aluminum hydride (LAH,547 mg, 14 mmol) and the mixture was stirred at 0° C. for 3 h and thenat room temperature for 1 h. The resulting mixture was cooled to 0° C.and 0.5 mL of water, 0.5 mL of a 15% NaOH solution, and 1.5 mL of waterwas successively added. The suspension was stirred for 0.5 h andfiltered through celite. The filtrate was concentrated to afford aresidue that was purified by flash chromatography (EtOAc), to yield thepure product as a colourless oil (4.45 g, yield:80% from the amine).

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.90 (s, 1H, triazole), 7.73 (s, 1H,triazole), 7.5-7.1 (m, 1H, arom), 7.33 (s, 5H, benzyl), 6.9-6.5 (m, 2H,arom), 4.77 (AB quartet, Δv=0.074, 2H, Tr-CH₂), 4.53 (s, 2H, CH₂ Ph),3.7-3.4 (m, 2H), 3.3-2.5 (m 3H), 0.90 (dd, J=1.2 Hz, J=7 Hz, 3H, CHMe).

REFERENCE EXAMPLE 3 (4R *,5 R*)-2-Benzyloxymethyl-4-methyl-5-[(1H-1,2,4-triazol-1-yl)methyl]-5-)2,4-dichlorophenyl) oxazolidine ##STR16##

Following the procedure described in reference example 1, but using(2R*,3R*)-3-amino-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-dichlorophenyl)-2-butanol(prepared as described in patent EP 332387) instead of its difluoroanalogue, the title compound was obtained in a similar yield and it wasused in the next step without further purification.

REFERENCE EXAMPLE 4(2R*,3R*)-3-[(2-Benzyloxyethyl)amino]-2-[2,4-dichlorophenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR17##

Following the procedure described in reference example 2, but reducingthe compound obtained in reference example 3, the title compound wasobtained as a white solid in 79% yield.

mp: 105°-107° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.82 (s, 1H, triazole), 7.68 (s, 1H,triazole), 7.49 (d, J=8.6 Hz, 1H, arom), 7.33 (s, 5H, benzyl), 7.10 (dt,Jd=2 Hz, Jt=12.8 Hz, 2H, arom), 5.22 (d, J=14.2 Hz, 1H, CH(H)), 4.71 (d,J=14.2 Hz, 1H, CH(H)), 4.55 (s, 2H, CH₂ Ph), 3.9-3.5 (m, 3H), 3.4-2.6(m, 2H), 0.80 (d, J=7 Hz, 3H, CHMe).

Analysis Calcd. for C21H24C12N302: C 57.94; H 5.56; N 12.87. Found: C58.29; H 5.74; N 12.53.

REFERENCE EXAMPLE 5(2R*,3R*)-3-[N-(Cyanomethyl)amino]-2-[2,4-difluorophenyl]-1-(1H-1,2,4-triazo1-1-yl)-2-butanol ##STR18##

To a mixture of methanol (130 mL), water (65 mL) and pH 7 phosphatebuffer (65 mL) it was added(2R*,3R*)-3-amino-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-2-butanol(400 mg, 14.9 mmol) (prepared as described in patent EP 332387),p-formaldehyde (490 mg, 16.4 mmol) and potassium cyanide (1.94 g, 29.82mmol). The resulting mixture was stirred at room temperature for 48 h.The mixture was concentrated to afford the desired product as an oilthat was purified by flash chromatography, to give a white solid in 78%yield.

mp: 138°-139° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.79 (s, 2H, triazole), 7.5-7.2 (m, 1H,arom), 6.9-6.6 (m, 2H, arom), 4.88 (s, 2H, Tr-CH₂), 3.71 (s, 2H, CH₂CN), 3.5-3.1 (m, 1Hm, CHMe), 0.96 (d, J=7 Hz, 3H, CHMe).

Analysis Calcd. for C₁₄ H₁₅ F₂ N₅ O: C 54.72; H 4.92; N 22.79. Found: C54.70; H 4.86; N 22.79.

REFERENCE EXAMPLE 6 (2R *,3R * )-3-[N-(2-Aminoethyl)amino]-2-[2,4-difluorophenyl ]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR19##

To a cooled (0° C.) solution of the product obtained in referenceexample (4.12 g, 13.4 mmol) in anhydrous THF (50 mL) was added lithiumaluminum hydride (509 mg, 13.4 mmol). The mixture was stirred for 2 h at0° C. and then water was slowly added, followed by 15% NaOH solution.The resulting suspension was stirred for some minutes and then filteredthrough celite. The filtrate was dried over anhydrous Na₂ SO₄, filteredand concentrated to afford the title compound as an oil in 69% yield.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.94 (s, 1H, triazole), 7.74 (s, 1H,triazole), 7.5-7.2 (m, 1H, arom), 6.9-6.6 (m, 2H, arom), 4.82 (dq AB,2H, Tr-CH₂), 3.2-2.5 (m, 5H), 0.92 (dd, J=l.2 Hz, J=7 Hz, 3H, CHMe).

REFERENCE EXAMPLE 7 (2R*,3R*)-3-[N-(2-Tert-butoxycarbonylaminoethyl)amino]-2-[2,4-difluoro-phenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR20##

To a solution of the product obtained in reference example 6 (2.5 g,8.03 mmol) in water (16 mL), dioxane (32 mL) and 1N NaOH (8 mL) wasadded BOC₂ O (1.75 g, 8.03 mmol). The mixture was stirred for 2 days atroom temperature and finally evaporated to dryness. The residue waspartitioned between water and EtOAc. The organic phase was dried overNa₂ SO₄, filtered and the solvent was removed to afford an oil that waspurified by flash chromatography (1.25 g, 37%).

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.93 (s, 1H, triazole), 7.75 (s, 1H,triazole), 7.5-7.2 (m, 1H, arom), 6.9-6.6 (m, 2H, arom), 4.83 (ABquartet, Δv=0.148, J=14.4 Hz, 2H, Tr-CH₂), 3.4-2.5 (m, 5H), 1.45 (s, 9H,CMe₃), 0.89 (d, J=7 Hz, 3H,Me).

REFERENCE EXAMPLE 8(2R*,3R*)-N-[3-(2,4-diflurophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]glycine,benzyl ester ##STR21##

A solution containing(2R*,3R*)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(14.9 g, 55.8 mmol) (prepared as described in patent EP 332387) in dryTHF (225 mL) was-treated at room temperature with benzylbromoacetate(19.2 g, 13.2 mL, 83.7 mmol, 1.5 eq) and triethylamine (15.5 mL, 111mmol, 2 eq) for 20 h which resulted in the appearance of a whiteprecipitate. The mixture was concentrated and partitioned between CHCl₃and 5% aqueous NaHCO₃. The aqueous phase was discarded and the organicphase was sequentially washed with more 5% aqueous NaHCO₃ and brine,dried over anhydrous Na₂ SO₄, filtrated and the filtrate wasconcentrated to an oil (29 g) which was purified by flash-chromatographyto afford the title product as a colorless oil (22.2 g, 95%).

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.85 (s, 1H, triazole), 7.74 (s, 1H,triazole), 7.6-7.2 (m, 1H, arom), 7.37 (s, 5H, benzyl), 6.9-6.6 (m, 2H,arom), 5.19 (s, 2H, CH₂ Ph), 4.83 (AB q, Δv=0.023, J=14.2 Hz, 2H,Tr-CH₂), 3.56 (s, 2H, CH₂ CO), 3.3-3.0 (m, 1H, CHMe), 0.90 (d, J=6.2 Hz,3H, CHMe).

REFERENCE EXAMPLE 9 (2R*,3R*)-N-[3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]glycine,ethyl ester ##STR22##

Following the procedure described in reference example 8, but startingfrom(2R*,3R*)-3-amino-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-dichlorophenyl)-2-butanol(obtained according to patent EP 332387) and using ethyl bromoacetateinstead of benzyl bromoacetate, the title compound was obtained in asimilar yield.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.88 (s, 1H, triazole), 7.73 (s, 1H,triazole), 7.52 (d, J=8.6Hz, 1H, arom), 7.30 (d, J=2.1Hz, 1H, arom),7.08 (dd, J=8.6Hz, J=2.1 Hz, 1H, arom), 5.13 (AB quartet, Δv=0.470,J=14.4 Hz, 2H, Tr--CH₂), 4.23 (q, J=7.1Hz, 2H, OCH? CH3), 3.74 (m, 1H,CHMe), 3.55 (s, 2H, CH₂ CO), 1.31 (t, J=7.1Hz, 3H, OCH₂ CH3), 0. 84 (d,J=6.6 Hz, 3H, CHMe).

REFERENCE EXAMPLE 10(2R*,3R*)-N-[3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]glycine,benzyl ester ##STR23##

Following the procedure described in reference example 8, but using(2R*,3R*)-3-amino-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-dichlorophenyl)-2-butanol(prepared as described in patent EP 332387) instead of its difluoroanalogue, the title compound was obtained in a similar yield.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.79 (s, 1H, triazole), 7.71 (s, 1H,triazole), 7.49 (d, J=8.6Hz, 1H, arom), 7.37 (s, 5H, phenyl), 7.27 (d,J=2.1Hz, 1H, arom), 7.06 (dd, J=8.6Hz, J=2.1 Hz, 1H, arom), 5.20 (s, 2H,CH₂ Ph), 5.07 (AB quartet, Δv=0.410, J=14.4 Hz, 2H, Tr--CH₂), 3.70 (q,J=6.5Hz, 1H, CHMe), 3.60 (s, 2H, CH₂ CO), 0.80 (d, J=6.5 Hz, 3H, CHMe).

REFERENCE EXAMPLE 11 1-[4-(Trifluoromethyl)phenyl]-1-propanol ##STR24##

Dry tetrahydrofuran (700 mL), magnesium turnings (16.75 g, 0.69 mol, 1.2eq), and a iodine crystal were placed in a flask and the mixture wasstirred intensively at 0° C. Bromoethane (68 g, 46.7 mL, 0.69 mol, 1.1eq) was added dropwise and the resulting mixture was allowed to stir for30 min. Then the reaction mixture was treated with4-trifluoromethylbenzaldehyde (100 g, 0.57 mol, 1 eq). After stirring atroom temperature for 2 h, the reaction mixture was cooled to 0° C. andpoured carefully to a mixture of 1N HCl (750 mL) and ice cooled to 0° C.and poured carefully to a mixture of 1N HCl (750 mL) and ice with CH₂Cl₂. The organic layer was washed with 5% aqueous NaHCO₃ and with CH₂Cl₂. The organic layer was washed with 5% aqueous NaHCO₃ and brine, thendried over anhydrous Na₂ SO₄, the drying agent was filtered and

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.52 (q, J=5.7 Hz, 4H, arom), 4.8-4.5(m, 1H, CHOH), 1.73 (q, J=6.8 Hz, 2H, CH₂), 0.92 (t, J=6.8 Hz, 3H, Me).

REFERENCE EXAMPLE 12 4-Trifluoromethylpropiophenone ##STR25##

A solution of the compound obtained in reference example 11 (23 g, 0.11mol) in CH₂ Cl₂ (60 mL) was added dropwise to a suspension of PCC (36.6g, 0.17 mol, 1.5 eq) and celite (35 g) in CH₂ Cl₂ (260 mL) at roomtemperature. The mixture was stirred for 1 h and then diethyl ether (500mL) was added. The resulting mixture was filtered through celite, washedwith aqueous NaOH solution, dried and concentrated to a dark brown oil(20.7 g, 95% mass balance) that was used in the next step withoutfurther purification.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.05 (d, J=8.2 Hz, 2H, arom), 7.71 (d,J=8.2 Hz, 2H, arom), 3.04 (q, J=7.1 Hz, 2H, CH₂), 1.24 (t, J=7.1 Hz, 3H,Me).

REFERENCE EXAMPLE 13 α-Bromo-4-trifluoromethylpropiophenone ##STR26##

To a solution of the compound obtained in reference example 12 (37 g,0.18 mol) in acetic acid (600 mL) was added dropwise a solution of 5%bromine in acetic acid (190 mL) at room temperature. When the additionwas complete, the reaction mixture was stirred at 40° C. for 2.5 h.Then, acetic acid was distilled off and the residue was diluted withEtOAc (300 mL) and washed with a 10% aqueous NaHCO₃ solution. Theorganic phase was dried over MgSO₄ and the solvent was removed to affordthe title compound as an oil (46.9 g, 93% mass balance).

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.13 (d, J=8.2Hz, 2H, arom), 7.74 (d,J=8.2 Hz, 2H, arom), 5.26 (q, J=6.6 Hz, 1H, CHBr), 1.92 (d, J=6.6 Hz,3H, Me).

REFERENCE EXAMPLE 14 α-Hydroxy-4-trifluoromethylpropiophenone ##STR27##

To a solution of the compound obtained in reference example 13 (45.9 g,0.16 mol) in a 4:1 mixture of DMF and H₂ O (460 mL) was added LiOH.H₂ O(6.9 g, 0.16 mol, 1 eq) at 0° C. and the resulting mixture was stirredfor 2 h. After diluting with EtOAc, the mixture was washed withsaturated aqueous NaCl solution, dried over anhydrous Na₂ SO₄, thedrying agent filtered and the filtrate concentrated in vacuo to afford39.81 g of a yellowish oil. Purification by chromatography on silica gel(EtOAc:Hex mixtures of increasing polarity) yielded 23.46 g of the titlecompound.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.05 (d, J=8.2Hz, 2H, arom), 7.74 (d,J=8.2 Hz, 2H, arom), 5.2 (Br q, 1H, CH), 1.45 (d, J=7Hz, 3H, Me).

REFERENCE EXAMPLE 15

α-(Tetrahydropyran-2-yloxy)-4-trifluoromethylpropiophenone ##STR28##

A mixture containing the compound obtained in reference example 14(23.46 g, 0.11 mol), 3,4-dihydro-2H-pyran (12.6 mL, 0.14 mol, 1.27 eq),pyridinium p-toluenesulfonate (0.006 mol) and CH₂ Cl₂ (260 mL) wasstirred at room temperature for 24 h. The reaction was quenched by theaddition of 10% aqueous NaHCO₃ solution and the layers were separated.The organic layer was washed with saturated NaCl solution, dried overanhydrous Na₂ SO₄, the drying agent was filtered and the filtrate wasconcentrated to afford a crude oil (28.6 g) that was used in the nextstep without further purification.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.2-7.9 (m, 2H, arom), 7.71 (d, J=8.2Hz, 2H, arom), 5.3-4.5 (m, 2H), 4.2-3.3 (m, 2H), 2.0-1.3 (m, 9H).

REFERENCE EXAMPLE 162-[2-(Tetrahydropyran-2-yloxy)ethyl]-2-[4-(trifluoromethyl)phenyl]oxirane##STR29##

A suspension of 55% NaH (2.7 g, 0.11 mol, 1.2 eq) was added to anhydrousDMSO (300 mL) and the mixture was heated at 60° C. for 1.5 h. Thereaction mixture was allowed to cool to room temperature andtrimethylsulfoxonium iodide (41.6 g, 0.19 mol, 2 eq) was added. Thereaction mixture was stirred at this temperature for 1 h. Next, thecompound obtained in reference example 15 (28.6 g, 0.09 mol) in DMSO(200 mL) was added dropwise. After stirring for 2 h, the mixture waspartitioned between benzene and water. The organic layer was separated,dried over anydrous Na₂ SO₄, the drying agent was filtered, and thefiltrate was concentrated in vacuo to afford a brown oil (29.7 g) thatwas directely used in the next step as such.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.60 (s, 4H, arom), 5.4-4.6 (m, 1H,OCHO), 4.4-3.2 (m, 3H), 3.1 (m, 1H, epoxide), 2.7 (m, 1H, epoxide),1.8-1.4 (m, 6H), 1.4-1.0 (m, 3H, Me).

REFERENCE EXAMPLE 17(2R*,3R*)-1-(1H-1,2,4-Triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-2,3-butane-diol##STR30##

The crude product obtained in reference example 16 (29.7 g) wasdissolved in DMF (300 mL) and then treated with 1,2,4-triazole (26.0 g,0.37 mol) and potassium tert-butoxide (21.12 g, 0.19 mol) at 100° C. for1 h. DMF was distilled off and the residue was partitioned betweenbenzene and water. The organic phase was separated, washed withsaturated NaCl solution, dried over anhydrous Na₂ SO₄, filtered and thefiltrate concentrated to afford a brown oil (36.28 g). This product wasthen dissolved in methanol (300 mL) and treated with p-toluenesulfonicacid (17.9 g, 0.094 mol) at room temperature for 2 h. 10% NaHCO₃solution was added and methanol was evaporated. The aqueous residue wasextracted with EtOAc, dried and concentrated to afford a brown solid.Recrystallization from EtOAc yielded the pure (2R*,3R*) stereoisomer asa white solid (8.41 g, 25% from ref. example 14).

mp: 177°-178° C.;

¹ H NMR (80 MHz, MeOH-d₄ +CDCl₃) δ (TMS): 7.98 (s, 1H, CH triazole),7.73 (s, 1H, CH triazole), 7.6-7.3 (m, 4H, arom), 4.72 (s, 2H, CH₂),4.16 (q, J=7.0Hz, 1H CHMe), 0.96 (d, J=7Hz, 3H, CHMe).

Analysis Calcd. for C₁₃ H₁₄ F₃ N₃ O₂ : C 51.83 H 4.68; N 13.95. Found: C51.96; H 4.63; N 13.61.

REFERENCE EXAMPLE 18(2R*,3R*)-3-Methanesulfonyloxy-2-[4-(trifluoromethyl)phenyl]-1-(1-H-1,2,4-triazol-1-yl)-2-butanol##STR31##

To a cooled solution (0° C.) of the compound obtained in referenceexample 17 (32 g, 106 mmol) in pyridine (500 mL) was addedmethanesulfonyl chloride (19.5 g, 13.2 mL, 170 mmol, 1.6 eq) and thereaction mixture was stirred at room temperature for 2 h. Next, pyridinewas distilled off and the residue was partitioned between CH₂ Cl₂ and10% aqueous NaHCO₃ solution. The organic phase was separated, dried overanhydrous Na₂ SO₄, the drying agent was filtered and the filtrate wasconcentrated to afford the desired product (38.39 g, 95% mass balance),pure by TLC analysis, which was used in the next step as obtained.

¹ H NMR (80 MHz, MeOH-d₄ +CDCl₃) δ (TMS): 8.00 (s, 1H, CH triazole),7.72 (s, 1H, CH triazole), 7.54 (s, 4H, arom), 5.16 (q, J=7Hz, 1H,CHMe), 4.77 (s, 2H, CH₂), 3.16 (s, 3H, MeSO₂), 1.24 (d, J=7Hz, 3H,CHMe).

REFERENCE EXAMPLE 19(2R*,3R*)-3-Azido-1-(1-H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-2-butanol##STR32##

A solution of the compound obtained in reference example 18 (38.39 g,101 mmol), sodium azide (34.24 g, 527mmol, 5.2 eq) and ammonium chloride(5.4 g, 101 mol, 1 eq) in DMF (500 mL) was heated at 115° C. for 15 h.DMF was distilled off, and the residue was partitioned between water(0.5 L) and benzene (0.5 L). The organic layer was washed with saturatedaqueous NaCl solution, dried over anhydrous Na₂ SO₄, the drying agentwas filtered and the filtrate was concentrated to afford the titlecompound of the example as a yellowish oil (37.44 g, 113% mass balance),pure by TLC analysis. An analytical sample was obtained byrecrystallization from EtOAc: Hex as a white solid.

mp: 91°-94° C.;

¹ H RMN (80 MHz, MeOH-d₄ +CDCl₃) δ (TMS): 7.82 (s, 1H, CH triazole),7.71 (s, 1H, CH triazole), 7.47 (AB q, Δv=0.16, J=8.4Hz, 4H, arom), 5.16(AB quartet, Δv=0.20, J=14.2Hz, 2H, TrCH₂), 3.70 (q, J=6.7Hz, 1H, CHMe),1.15 (d, J=6.7Hz, CHMe).

Analysis Calcd. for C₁₃ H₁₃ F₃ N₆ O: C 47.86; H 4.02; N 25.76. Found: C47.12; H 3.76; N 22.68.

REFERENCE EXAMPLE 20 (2R*,3R*)-3-Amino-1-(1-H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-2-butanol##STR33##

A suspension of the compound obtained in reference example 19 (37.44 g)and 10% Pd/C (7 g) in ethanol (1 L) was hydrogenated (H₂, 1 atm) at roomtemperature for 1 h with intensive stirring. The resulting mixture wasfiltered through celite and concentrated to afford the correspondingamine as a pale solid (26.97 g, 85% from the diol). An analytical samplewas obtained as a white powder by flash-chromatography (CHCl₃ : MeOH9:1) and recrystallization from EtOAc: hexane.

mp: 114°-117° C.;

¹ H NMR (80 MHz, MeOH-d₄ +CDCl₃) δ (TMS): 7.88 (s, 1H, CH triazole),7.86 (s, 1H, CH triazole), 7.47 (AB quartet, Δv=0,175, J=8.5 Hz, 4H,arom), 4.53 (s, 2H, CH₂), 3.38 (q, J=7Hz, 1H, CHMe), 0.85 (d, J=7Hz, 3H,CHMe).

Analysis Calcd. for C₁₃ H₁₅ F₃ N₄ O: C 51.98; H 5.04; N 18.66. Found: C51.92; H 5.06; N 18.62.

REFERENCE EXAMPLE 21(2R*,3R*)-N-[3-(4-Trifluoromethylphenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]glycine,benzyl ester ##STR34##

Following the procedure described in reference example 8, but startingfrom the compound obtained in reference example 20, the title compoundwas obtained in 90% yield.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.91 (s, 1H, triazole), 7.80 (s, 1H,triazole), 7.6-7.2 (m, 4H, arom), 7.37 (s, 5H, benzyl), 5.29 (s, 2H, CH₂Ph), 4.73 (AB quartet, Δv=0.308, J=14.3 Hz, 2H, Tr--CH₂), 3.51 (ABquartet, Δv=0.090, J=17.8Hz, 2H, CH₂ CO), 2.82 (q, J=6.6Hz, 1H, CHMe),0.96 (d, J=6.6 Hz, 3H, CHMe).

REFERENCE EXAMPLE 22(2R,3R)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]glycine,benzyl ester ##STR35##

Following the procedure described in reference example 8, but using(2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(prepared as described in EP 332387) the title compound was prepared asan oil. The NMR spectrum of the compound thus prepared was identical tothat of the compound obtained in reference example 8.

REFERENCE EXAMPLE 23

(2R,3R)-N-[3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]glycine,benzyl ester ##STR36##

Following the procedure described in reference example 10 but using(2R,3R)-3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(pre-pared as described in EP 332387) the title compound was obtained asan oil. The NMR spectrum of the compound thus prepared was identical tothat of the compound obtained in reference example 10.

[α]_(D) -94.4° (c=1, MeOH)

REFERENCE EXAMPLE 24(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-DL-alanine,benzyl ester ##STR37##

Following the procedure described in reference example 10 but usingbenzyl 2-bromopropionate instead of benzylbromoacetate and increasingthe reaction time to 7 days of stirring at room temperature, the titlecompound was obtained in 54% yield as an oil as a 1:1 mixture ofdiastereomers.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.81 (s, 1H, triazole), 7.74 (s, 1H,triazole), 7.5-7.2 (m, 1H, arom), 7.36 (s, 5H, benzyl), 6.9-6.6 (m, 2H,arom), 5.18 (s, 2H, CH₂ Ph), 5.1-4.5 (m, 4H,) 3.7-3.3 (m, 1H, CHMe),1.35 (dd, JC-F=2Hz, J=7Hz, 3/2H, CHMe), 0.85 (dd, JC-F=2Hz, J=7Hz, 3/2H,CHMe).

REFERENCE EXAMPLE 25(4R*,SR*)-2-Chloromethyl-4-methyl-5-[(1-H-1,2,4-triazol-1-yl)methyl]-5-(2,4-5dichlorophenyl) oxazolidine ##STR38##

Following the procedure described in reference example 1, but using a45% aqueous solution of chloroacetaldehyde and(2R*,3R*)-3-amino-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-dichlorophenyl)-2-butanol,the title compound was obtained as a solid in 63% yield afterflash-chromatography purification (EtOAc).

mp: 119°-125° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.32(s, 1H, triazole), 7.68 (s, 1H,triazole), 7.4-7.0 (m, 3H, arom), 5.60 (d, J=14Hz, 1H, CH(H)), 5.12 (t,J=2Hz, 1H, CHO), 4.6 (d, J=14Hz, 1H, CH(H)), 4.39 (q, J=7Hz, 1H, CHMe),3.96 (d, J=2Hz, 1H, CH(H)Cl), 3,92 (d, J=2Hz, 1H, CH(H)Cl), 1.00 (d,J=7Hz, 3H, Me).

Anal. Calcd. for C₁₄ H₁₅ Cl₃ N₄ O: C 46.50; H 4.I8; N 15.49. Found: C46.32; H 3.88; N 15.81.

REFERENCE EXAMPLE 26(4R*,SR*)-2,5-bis-[(1-H-1,2,4-Triazol-1-yl)methyl]-4-methyl-5-(2,4-dichlorophenyl)oxazolidine ##STR39##

A solution containing the product obtained in reference example 25 (750mg, 2 mmol), 1,2,4-triazole (0,286 g, 4.1 mmol, 2 eq), and K₂ CO₃ (0.572g, 4.1 mmol, 2 eq) in DMF (40 mL) was stirred at 90° C. during 5 h. Thesolvent was removed under reduced pressure and the residue waspartitioned between CHCl₃ and a 5% NaHCO₃ aqueous solution. The organicphase was separated, dried over MgSO₄, concentrated and purified byflash-chromatography to afford the title product as a mixture ofdiastereomers at the acetal carbon (0.69 g, 87%).

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.33 (s, 1H, triazole), 8.19 (s, 1H,triazole), 8.01 (s, 1H, triazole), 7.95 (s, 1H, triazole), 7.81 (s, 1H,triazole), 7.74 (s, 1H, triazole), 7.71 (s, 1H, triazole), 7.5-7.0 (m,3H, arom), 5.13 (complex t, 1H, CHO), 5.0-4.7 (m, 2H), 4.5-4.1 (m, 4H),0.95 and 0.84 (d, J=7Hz, 3H, Me).

REFERENCE EXAMPLE 27 (2R*,3R*)-3-[(2-(1H-1,2,4-Triazo1-1-yl)ethyl)amino]-2-(2,4-dichloro (1H-1,2,4-triazo1-1-yl)-2-butanol##STR40##

Following the procedure described in reference example 2 but reducingthe product obtained in reference example 26, the title product wasobtained as a yellowish oil that was used in the next step withoutfurther purification.

REFERENCE EXAMPLE 28 (3(2R,3R) ,4S)-3-[3-(2,4-Difluorophenyl)-3,4-epoxy-2-methyl-1-oxobutyl]-4-benzyl-2-oxazolidinone##STR41##

To a cooled (-78° C.) solution containing sodiumbis(trimethylsilyl)amide (394 mg, 2.15 mmol, 1 eq) in dry THF (8 mL) wasadded a solution of (45)-3-propionyl-4-benzyl-2-oxazolidinone (500 mg,2.15 mmol) (prepared from propionyl chloride and(45)-4-benzyl-2-oxazolidinone, which, in turn, was purchased in Kgquantities to Urquima S. A., Sant Fost de Capcentelles, Barcelona,Spain) in dry THF (2 mL) and the mixture was stirred at this temperaturefor 1.5 h. Then, a solution of α-bromo-2,4-difluoroacetophenone (606 mg,2.6 mmol, 1.2 eq) in THF (2 mL) was slowly added and the mixture wasstirred at -78° C. during 2 h. The reaction was quenched by the additionof a saturated NH₄ Cl aqueous solution and the volatiles were removed invacuo. The aqueous residue was then partitioned between CH₂ Cl₂ andwater. The aqueous phase was discarded and the organic phase was washedwith 5% aqueous NaHCO₃ and brine, then dried over anhydrous Na₂ SO₄, thedrying agent was filtered and the filtrate was concentrated to acream-colored oil (1.2 g). RMN analysis of the crude product indicatedformation of a main epoxide (i.e. the title compound) and a minor isomerwhich was proved to have an anti relative stereochemistry. An analyticalsample of the diastereomerically pure title product was obtained bysilica gel chromatography (EtOAc:Hex 1:5) of an aliquot of 120 mg ofcrude reaction mixture as a colorless, thick oil (47 mg, 57%).

¹ H RMN (80 MHz, CDCl₃) 15 (TMS) 7.6-6.6 (complex signal, 8H, arom),4.8-4.4 (m, 1H, NCH), 4.62 (q, J=7Hz, 1H, CHMe), 4.3-3.9 (m, 2H, NCHCH₂O), 3.24 (dd, J=3.5Hz, J=13.3Hz, 1H, CH(H)Ph), 3.24 (d, l=4.7Hz, 1H,epox CH(H)), 2.95 (d, J=4.7Hz, 1H, epox. CH(HH)), 2.57 (dd, J=9.5Hz,J=13.3Hz, 1H, CH(HH)Ph), 1,19 (d, J=7Hz, 3H, Me)

REFERENCE EXAMPLE 29(2R,3R)-3-(2,4-Difluorophenyl)-3,4-epoxy-2-methylbutanoic acid ##STR42##

To a cooled (-5° C.) solution containing the unpurified aldol productobtained in reference example 28 (2 g) in a 4:1 mixture of THF:H₂ O (40mL) it was added a solution containing LiOH (0.325 g, 7.8 mmol) and 35%aqueous solution of H₂ O₂ (2 mL, 21 mmol) in water (8 mL). The reactionwas stirred at 0° C. for 2 h. Then, a solution containing Na₂ SO₃ (2.6g, 21 mmol) in H₂ O (10 mL) was added and the volatiles were removed invacuo. The alkaline aqueous residue was taken up with CH₂ Cl₂ (3x) andthe aqueous phase was then brought to pH 1 by addition of aqueous 2N HCland extracted (3x) with CH₂ Cl₂. The combined organic phases were driedover anhydrous Na₂ SO₄, filtered and the filtrate was concentrated underreduced pressure to a white semisolid containing the title product (0.50g).

¹ H RMN (80 MHz, CDCl₃) δ (TMS) 10-8.5 (br, 1H, CO2H), 7.6-7.2 (complexsignal, 1H, arom), 7.1-6.6 (complex signal, 2H, arom), 3.15 (d, J=4.7Hz,1H, epox. CH(H)), 3.02 (q, J=7.3Hz, 1H, CHMe), 2.82 (d, J=4.7Hz, 1H,CH(H)), 1.20 (dd, J_(C) F=0.8Hz, J_(d) =7.3Hz, 3H, Me).

REFERENCE EXAMPLE 30 (2R ,3 R)-3-(2,4-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoicacid. ##STR43##

To a cooled (0° C.) suspension of Nail (55% mineral oil dispersion, 288mg, 6.6 mmol, washed with hexane) in DMF (25 mL) was added1,2,4-triazole (0.5 g, 7.2 mmol) and the mixture was stirred at 0° C.until hydrogen gas ceased to evolve. Then, a solution of unpurified(2R,3R)-3-(2,4-difluorophenyl)-3,4-epoxy-2-methylbutanoic acid (0.5 g)(obtained in reference example 29) in DMF (3 mL) was slowly added andthe mixture was heated to 60° C. during 2 h. A saturated NH₄ Cl aqueoussolution was then added and the solvents were removed in vacuo. Themixture was then partitioned between brine containing AcOH and EtOAc.The organic layer was separated and the aqueous phase was extracted withmore EtOAc (3x). The collected organic fractions were then dried overanhydrous Na₂ SO₄, the drying agent was filtered and the filtrate wasconcentrated under reduced pressure to a white solid. Recrystallizationfrom EtOAc afforded the title product as a white solid.

mp: 162°-164° C.;

¹ H RMN (80 MHz, DMSO-d₆) δ (TMS) 8.25 (s, 1H, triazole), 7.57 (s, 1H,triazole), 7.4-6.7 (complex signal, 3H, arom), 4.67 (AB quartet,Δv=0.12, J=14.3Hz, 2H, CH₂ Tr), 2.96 (br q, J=7.1Hz, 1H, CHMe), 0.80 (d,J=7.1Hz, 3H, Me)

REFERENCE EXAMPLE 31(2R,3R)-3-Amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR44##

A solution of(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoicacid (50 mg, 0.17 mmol) (obtained in reference example 30) andtriethylamine (0.35 mL, 0.25 mmol) in tert-butanol (3 mL) was treatedwith diphenylphosphoryl azide (0.44 mL, 0.20 mmol) and the reactionmixture was heated at reflux for 25 h. Removal of the volatiles underreduced pressure afforded a crude product that was partitioned betweenchloroform and saturated NaHCO₃ aqueous solution. The organic phase wasdried over anhydrous Na₂ SO₄, filtered and the filtrate was concentratedin vacuo to a brown oil that was dissolved in methanol (2 mL) and 1Naqueous KOH (1 mL) and then heated at 70° C. during 15 h. The volatileswere removed in vacuo and the aqueous residue was acidified to pH 1 byaddition of 1N aqueous HCl and washed with CHCl₃. The aqueous phase wasbasified with saturated Na₂ CO₃, saturated with NaCl and extracted (3x)with CHCl₃. The collected organic phases were dried over anhydrous Na₂SO₄, the drying agent was filtered and the filtrate was concentrated toafford the title product (18.8 mg) pure by TLC analysis. An analyticalsample was obtained by chromatography on silica gel (CHCl₃ : MeOH 5:1)as a white solid.

mp: 156°-157° C.;

¹ H RMN (80 MHz, CDCl₃) δ (TMS) 7.96 (s, 1H, triazole), 7.78 (s, 1H,triazole), 7.7-7.3 (m, 1H, arom), 7.0-6.6 (m, 2H, arom), 4.67 (s, 2H,CH₂ Tr), 3.61 (dq, J_(CF) =2.8Hz, J_(q) =6.5Hz, 1H, CHMe), 0.85 (d,J=6.5Hz, 3H, Me);

[α]_(D) -72.6° (c=1, CHCl₃); [lit [α]_(D) -73° (c=1.06, CHCl₃)] (Chem.Pharm. Bull., 1991, 39, 2581-2589)

Analysis Calcd. for C₁₂ H₁₄ F₂ N₄ O: C 53.72, H 5.26, N 20.88. Found: C53.38; H 5.32, N 21.24.

EXAMPLE 1(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[N-[4-(trifluoromethyl)benzoyl]-N-(2-benzyloxyethyl)amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR45##

To a solution of(2R*,3R*)-3-[(2-benzyloxyethyl)amino]-2-[2,4-difluorophenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol(4.40 g, 11.4 mmol) (obtained as described in reference example 2) inCH₂ Cl₂ (40 mL) was added triethylamine (1.74 mL, 12.5 mmol). Theresulting mixture was cooled in an ice bath and a solution of4-(trifluoromethyl)benzoyl chloride (2.61 g, 12.5 mmol) in CH₂ Cl₂ (5mL) was carefully added and the mixture was stirred for 1 h at 0° C. andthen for 18 h at room temperature. The resulting solution was dilutedwith CH₂ Cl₂ and washed with 5% aqueous NaHCO₃ solution. The organicphase was separated, dried over Na₂ SO₄ and the solvent was removed, toafford a thick oil (9.17 g) that was purified by chromatography onsilica gel (EtOAc: hexane 1:1). The title compound of the example wasobtained as a white foam.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.9-7.1 (m, 12H, arom), 6.9-6.5 (m, 2H,arom), 5.06 (d, J-14 Hz, 1H, CH(H)), 4.54 (s, 2H, CH₂ Ph), 4.6-3.5 (m,6H), 1.5-1.0 (m, 3H, CHMe).

Analysis Calcd. for C₂₉ H₂₇ F₅ N₄ O₃ : C 60.62; H 4.74; N 9.75. Found: C60.43; H 4.69; N 9.32.

EXAMPLE 2

(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[N-(2-benzyloxyethyl)-N-[4-(trifluoromethyl)benzoyl]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol,oxalate ##STR46##

To a solution of the product obtained in example 1 in EtOAc was added asolution of oxalic acid in EtOAc. A little ether was added and theresulting solution was then allowed to precipitate at -20° C. overnight.The solid thus obtained was filtered and dried to afford the oxalate asa white solid.

mp: 56°-63° C.;

Analysis Calcd. for C₂₉ H₂₇ F₅ N₄ O₃.C₂ O₄ H₂.2H₂ O: C 53.15; H 4.75; N7.00.

Found: C 53.23; H 4.21; N 7.67.

EXAMPLE 3(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[N-(2-hydroxyethyl)-N-[4-(trifluoromethyl)-benzoyl]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR47##

A mixture of the product obtained in example 1 (1.68 g, 2.9 mmol), 10%palladium on charcoal (420 mg) and ethanol (20 mL) was hydrogenated at 1atm under vigorous stirring for 18 h. The mixture was filtered throughcelite and washed with ethanol. The filtrate was concentrated and theresidue was purified by flash chromatography (EtOAc: Hex 4:1, then 1:0)to give the pure product as a white solid (718 mg, yield: 51%)

mp: 167°-168° C.;

¹ H NMR (80 MHz, DMSO-d₆) δ (TMS): 8.30 and 8.17 (s, 1H, triazole),8.0-6.7 (m, 8H, arom), 5.02 (br d, J=14 Hz, 1H, CH(H)), 4.8-4.1 (m),3.9-3.3 (m), 1.3-1.0 (d J=7Hz, CHMe, 3H).

MS (DIP, CI, CH₄): M⁺ +1=485

Analysis Calcd. for C₂₂ H₂₁ F₅ N₄ O₃ : C 54.55; H 4.37; N 11.57. Found:C 54.91; H 4.42; N 11.23.

EXAMPLE 4(2R*,3R*)-2-[2,4-Difluorophenyll-3-[N-(2-hydroxyethyl)-N-[4-(trifluoromethyl)-benzoyl]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol,oxalate ##STR48##

To a solution of the product obtained in example 3 in EtOAc was added asolution of oxalic acid in EtOAc, and the resulting solution was thenallowed to precipitate at -20° C. overnight. The precipitate wasfiltered and dried to afford the oxalate as a white solid.

mp: 120°-122° C.;

Analysis Calcd. for C₂₂ H₂₁ F₅ N₄ O₃.C₂ O₄ H₂ : C 50.18; H 4.04; N 9.75.Found: C 49.99; H 3.95; N 9.64.

EXAMPLE 5(2R*,3R*)-2-[2,4-Dichlorophenyl]-3-[N-[4-(2,2,3,3-tetrafluoropropoxy)benzoyl]-N-(2-benzyloxyethyl)amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR49##

Following the procedure described in example 1, but starting from thecompound obtained in reference example 4 and using4-(2,2,3,3-tetrafluoropropoxy)benzoyl chloride (obtained according topatent EP 472392), the title compound of the example was isolated as awhite solid.

mp: 51°-62° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.30 (s, 1H, triazole), 7.9-6.8 (m,triazole, arom), 6.05 (tt, J=4.8Hz, J=53Hz, 1H, CF₂ H), 5.6-5.3 (m),4.7-3.8 (m), 3.72 (s), 1.26 and 1.05 (d, J=6.8Hz, 3H, CHMe).

Analysis Calcd. for C₃₁ H₃₀ Cl₂ F₄ N₄ O₄ : C 55.61; H 4.52; N 8.37.Found: C 55.69; H 4.66; N 8.31.

EXAMPLE 6(2R*,3R*)-2-[2,4-Dichlorophenyl]-3-[[N-[4-(2,2,3,3-tetrafluoropropoxy)benzoyl]-N-(2-hydroxyethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR50##

Following the procedure described in example 3, but hydrogenating thecompound obtained in example 5, the title compound was obtained as awhite wax.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.29 (s), 8.1-6.9 (m, triazole, arom),6.06 (tt, J=4.6 Hz, J=53 Hz, 1H, CF₂ H), 5.5-5.0 (m), 5.0-3.5 (m), 1.27and 1.06 (d, J=7 Hz, 3H, CHMe).

Analysis Calcd. for C₂₄ H₂₄ Cl₂ F₄ N₄ O₄ : C 49.75; H 4.18; N 9.67.Found: C 50.02; H 4.41; N 9.99.

EXAMPLE 7(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[[N-[4-(trifluoromethyl)benzoyl]-N-(2-acetoxyethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR51##

To a solution of(2R*,3R*)-2-[2,4-difluorophenyl]-3[[N-[4-(trifluoromethyl)benzoyl]-N-(2-benzyloxyethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (0.26 g, 0.53 mmol) (obtained asdescribed in example 1) in 5 mL of CH₂ Cl₂, was added triethylamine(0.09 mL, 0.67 mmol). The resulting mixture was cooled in an ice bath,acetyl chloride was added (0.042 mL, 0.59 mmol) and the mixture wasstirred for 2 h at 0° C. The mixture was diluted with CH₂ Cl₂ and washedwith 5% NaHCO₃ aqueous solution. The organic phase was separated, driedover Na₂ SO₄ and the solvent was removed, to afford a thick oil that waspurified by chromatography on silica gel (EtOAc: Hex 3:1). The titlecompound was obtained as a white solid (180 mg).

mp: 152°-153° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.9-7.5 (m, 7H, triazole, arom),7.0-6.6 (m, 2H, arom), 5.3-3.5 (m, 7H), 2.06 (s, 3H, Ac), 1.4-1.1 (m,3H, CHMe).

Analysis Calcd. for C₂₄ H₂₃ F₅ N₄ O₄ : C 54.76; H 4.40; N 10.64. Found:C 54.89; H 4.41; N 10.21.

EXAMPLE 8(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[[N-[4-(trifluoromethyl)benzoyl]-N-(2-(4-trifluoromethylbenzoyloxy)ethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butano##STR52##

Following the procedure described in example 7, but using4-(trifluoromethyl)benzoyl chloride instead of acetyl chloride, thetitle compound of the example was obtained in a similar yield.

mp: 55°-60° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.4-7.5 (m, 11H, triazole, arom),6.9-6.6 (m, 2H, arom), 5.4-3.7 (m, 7H), 1.4-1.1 (m, 3H, CHMe).

Analysis Calcd. for C₃₀ H₂₄ F₈ N₄ O₄ : C 54.88; H 3.68; N 8.53. Found: C55.04; H 3.96; N 8.45.

EXAMPLE 9 (2R*,3R*)-2-[2,4-Dichlorophenyl]-3-[[N-[4-(trifluoromethyl)benzoyl]-N-(2-benzyloxyethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR53##

Following the procedure described in example 1, but using the compoundobtained in reference example 4, the title compound of the example wasobtained as a white solid.

mp: 96°-97° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.9-7.0 (m, 14H, triazole, arom), 5.52(d, J=14 Hz, CH(H)), 4.8-4.4 (m), 4.1-3.8 (m, 1H), 3.67 (s, 2H, CH₂ Ph),1.28 and 1.03 (d, J=6.8 Hz, CHMe).

Analysis Calcd. for C₂₉ H₂₇ Cl₂ F₃ N₄ O₃ : C 57.34; H 4.48; N 9.22.Found: C 57.47; H 4.45; N 9.15.

EXAMPLE 10(2R*,3R*)-2-[2,4-Dichlorophenyl]-3-[N-(2-hydroxyethyl)-N-[4-(trifluoromethyl)-benzoyl]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR54##

Following the procedure described in example 3, the product of example 9was hydrogenated to afford the title compound as a white solid in asimilar yield.

mp: 185°-189° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.0-7.0 (m, 9H, triazole, arom),5.5-4.5 (m), 4.4-3.5 (m), 1.29 and 1.06 (d, J=7 Hz, CHMe).

Analysis Calcd. for C₂₂ H₂₁ C₁₂ F₃ N₄ O₃ : C 51.08; H 4.09; N 10.83.Found: C 51.47; H 4.05; N 10.70.

EXAMPLE 11(2R*,3R*)-3-[N-(2-tert-Butoxycarbonylaminoethyl)-N-[4-(trifluoromethyl)-benzoyl]amino]-2-[2,4-difluorophenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR55##

Following the procedure described in example 1, but using the compoundobtained in reference example 7, the title compound of the example wasobtained as a white solid.

mp: 135°-143° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.8-7.4 (m, 7H, triazole, arom),7.0-6.7 (m, 2H, arom), 5.5-5.0 (m, 3H), 4.6-4.3 (m, 2H), 3.6-3.3 (m,1H), 3.14 (s, 3H), 1.56 and 1.41 (s, 9H, CMe₃), 1.3-1.1 (m, 3H, CHMe).

Analysis Calcd. for C₂₇ H₃₀ F₅ N₅ O₄ : C 55.57; H 5.18; N 12.00. Found:C 55.44; H 4.52; N 11.42.

EXAMPLE 12 (2R*,3R*)-3-[N-(2-Aminoethyl)-N-[4-(trifluoromethyl)benzoyl]amino]-2-[2,4-difluorophenyl]-1-(1H-1,2A-triazol-1-yl)-2-butanol##STR56##

A solution containing the compound obtained in example 11 (0.5 g) wastreated with a saturated solution of HCl in methanol (12 mL) at refluxfor 3 h. The mixture was concentrated and the residue partitionedbetween EtOAc and 10% NaHCO₃ solution. The organic phase was dried, thesolvent was removed and the residue was purified by flash chromatography(EtOAc:Hex 4:1), to give 97 mg of pure product.

mp: 230°-235° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.8-7.4 (m, 7H, triazole, arom),7.0-6.7 (m, 2H, arom), 5.5-4.5 (m), 4.4-3.7 (m), 3.7-3.3 (m), 3.4-2.5(m), 1.5-0.9 (m, 3H, CHMe).

HPLC-MS (CI, CH₄): M⁺ +1=484

Analysis Calcd. for C₂₂ H₂₂ F₅ N₅ O₂ : C 54.66; H 4.59; N 14.49. Found:C 54.80; H 4.43; N 13.74.

EXAMPLE 12A

(2R*, 3R*)-3-[N-(2-Aminoethyl)-N-[4-(trifluoromethyl)benzoyl]amino]-2-[2,4-dichlorophenyl]-1-1,2,4-triazol-1-yl)-2-butanol,and the homochiral (2R,3R) compound, are prepared in a manner analogousto the described preparation of the 2,4-difluorophenyl compound ofExample 12.

EXAMPLE 13(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-2-hydroxy-4-[4-(trifluoromethyl)-benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholine##STR57##

Method A: To a cooled (-78° C.) solution containing oxalyl chloride(0.093 mL, 1.08 mmol) in CH₂ Cl₂ (5 mL) was added dropwise anhydrousDMSO (0.15 mL, 2.17 mmol). Ten minutes after, it was added a solution of(2R*,3R*)-2-[2,4-difluorophenyl]-3-[N-(2-hydroxyethyl)-N-[4-(trifluoromethyl)benzoyl]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (obtained in example3) (420 mg, 0.87 mmol) in DMSO--CHCl₃. The mixture was stirred during 30min, after which period freshly distilled triethylamine (0.6 mL, 4.33mmol) was added. The reaction flask was then let warm to -40° C. and themixture was stirred at this temperature for 1 h and at -10° C. during 30min. A 0.5M NaHSO₄ solution was then added and the organic phase waswashed with water and brine. Drying over anhydrous Na₂ SO.sub. 4,filtration and concentration gave a crude product that waschromatographed on silica gel (EtOAc: Hex 4:1) to afford the titleproduct as a white solid (145 mg, 34% yield).

Method B: Alternatively, this compound may also be obtained by thefollowing method: a solution of(2R*,3R*)-2-[2,4-difluorophenyl]-3-[[N-[4-(trifluoromethyl)benzoyl]-N-(2-hydroxyethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol(250 mg, 0.51 mmol) (obtained according to example 3) in acetone (5 mL)was treated with tris(triphenylphosphine)ruthenium (II) chloride (10 mg)and N-methylmorpholine N-oxide (250 mg, 2.1 mmol) at room temperaturefor 20 h. The mixture was concentrated and the residue purified by flashchromatography (EtOAc: Hex 4:1) to give the title compound as a whitesolid (75 mg).

mp: 193°-195 ° C.;

¹ H NMR (80 MHz, MeOH-d₄) δ (TMS): 8.0-7.2 (m, 7H, triazole, arom),7.0-6.6 (m, 2H, arom), 5.9-5.3 (m, 2H, Tr--CH(H), OCHOH), 5.2-4.2 (m,2H, Tr--CH(H), CHMe), 3.7 (br s, 2H, OCHCH₂), 1.13 (d, J=6.8Hz, 3H,CHMe.).

Analysis Calcd. for C₂₂ H₁₉ F₅ N₄ O₃ : C 54.78; H 3.97; N 11.61. Found:C 54.48; H 3.98; N 11.87.

EXAMPLE 14(2R*,3R*)-3-[N--Cyanomethyl-N-(4-trifluoromethylbenzoyl)amino]-2-[2,4-difluorophenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol,oxalate ##STR58##

Following the procedure described in example 1, but using the compoundobtained in reference example 5 and subsequently preparing the oxalate,the title compound of the example was obtained as a white solid.

mp: 131°-133° C.;

¹ H NMR (80 MHz, MeOH-d4) δ (TMS): 8.25 (s, 1H, triazole), 8.0-7.5 (m,5H, triazole, arom), 7.5-7.1 (m, 1H, arom), 7.0-6.6 (m, 2H, arom), 4.76(s, 4H, Tr--CH₂, CH₂ CN), 4.9-4.5 (m, 1H, CHMe), 1.23 (d, J=7 Hz, 3H,CHMe).

Analysis Calcd. for C₂₂ H₁₈ F₅ N₅ O₂.C₂ O₄ H₂.H₂ O: C 49.07; H 3.77; N11.92.

Found: C 48.52; H 3.57; N 11.81.

EXAMPLE 15(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[[N-[4-(2,2,3,3-tetrafluoropropoxy)benzoyl]-N-(2-benzyloxyethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR59##

Following the procedure described in example 1, but using4-(2,2,3,3-tetrafluoropropoxy)benzoyl chloride (obtained according topatent EP 472392) instead of 4-(trifluoromethyl)benzoyl chloride, thetitle compound was obtained.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.20 (s, 1H, triazole), 7.7-7.2 (m,triazole, arom), 7.1-6.1 (m, arom), 6.06 (tt, J=4.7Hz, J=53Hz, 1H, CF₂H), 5.03 (d, J=14.4Hz, 1H, CH(H)-Tr) 4.7-4.1 (m), 3.9-3.5 (m), 1.4-1.0(m, 3H, CHMe).

EXAMPLE 16(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[[N-[4-(2,2,3,3-tetrafluoropropoxy)benzoyl]-N-(2-hydroxyethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR60##

Following the procedure described in example 3, but using the compoundobtained in example 15, the title compound was obtained.

mp: 156°-157° C.;

¹ H NMR (80 MHz, CDCl₃)δ (TMS): 8.26 (s, 1H, triazole), 8.0-6.6 (m, 8H,triazole, arom), 6.06 (tt, J=4.7Hz, J=53Hz, 1H, CF₂ H), 5.1-3.6 (m),1.4-1.0 (m, 3H, CHMe);

Analysis Calcd. for C₂₄ H₂₄ F₆ N₄ O₄ : C 52.75; H 4.43; N 10.25. Found:C 53.16; H 4.61; N 9.88.

EXAMPLE 17(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-2-hydroxy-4-[4-(2,2,3,3-tetrafluoropropoxy)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholine##STR61##

Following the Method A described in example 13, but using the compoundobtained in example 16, the title compound of the example was obtained.

mp: 209°-210° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.85 (s, 1H, triazole), 7.70 (s, 1H,triazole), 7.6-6.8 (m, 7H, arom), 6.06 (tt, J=4.8Hz, J=53Hz, 1H, CF₂ H),5.9-5.4 (m, 2H), 5.2-4.5 (m, 2H), 4.41 (dt, J=11.9Hz, J=1.4Hz, 2H, CH₂CF₂), 4.0-3.1 (m, 2H), 1.10 (d, J=6.8Hz, 3H, CMe);

Analysis Calcd. for C₂₄ H₂₂ F₆ N₄ O₄ : C 52.95; H 4.07; N 10.29. Found:C 53.20; H 4.22; N 10.17.

EXAMPLE 18(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[[N-[4-(trifluoromethoxy)benzoyl]-N-(2-benzyloxyethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR62##

Following the procedure described in example 1, but using4-(trifluoromethoxy)benzoyl chloride instead of4-(trifluoromethyl)benzoyl chloride, the title compound was obtained.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.22 (s, 1H, triazole), 7.7-7.1 (m,11H, triazole, arom), 6.9-6.5 (m, 2H, arom), 5.04 (br d, J=14.4Hz, 1H,CH(H)Tr), 4.56 (s, 2H, CH₂ Ph), 4.7-3.4 (m, 6H), 1.4-1.0 (m, 3H, CHMe).

EXAMPLE 19(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[[N-[4-(trifluoromethoxy)benzoyl]-N-(2-hydroxyethyl)]amino]-1-(1H-1,2,4-triazo1-1-yl)-2-butanol ##STR63##

Following the procedure described in example 3, but using the compoundobtained in example 18, the title compound was obtained.

mp: 145°-146° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.27 (s, 1H, triazole), 8.0-7.1 (m, 6H,triazole, arom), 7.0-6.5 (m, 2H, arom), 5.1-4.4 (m), 4.3-3.6 (m),1.4-1.0 (m, 3H, CHMe);

Analysis Calcd. for C₂₂ H₂₁ F₅ N₄ O₄ : C 52.80; H 4.23; N 11.20. Found:C 52.55; H 4.17; N 10.80.

EXAMPLE 20(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[[N-[4-(2,2,2-trifluoroethoxy)benzoyl]-N-(2-benzyloxyethyl)lamino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR64##

Following the procedure described in example 1, but using4-(2,2,2-trifluoroethoxy)benzoyl chloride instead of4-(trifluoromethyl)benzoyl chloride, the title compound was obtained.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.19 (s, 1H, triazole), 7.7-7.2 (m,triazole, arom), 7.31 (s, 5H, benzyl), 6.95 (d, J=8.7Hz, 2H, arom),6.8-6.5 (m, 2H, arom), 5.03 (br d, J=14.4Hz, 1H, CH(H)Tr), 4.8-4.0 (m,2H), 4.57 (s, 2H, CH₂ Ph), 4.39 (q, J=8.1Hz, 2H, CH₂ CF₃), 4.0-3.5 (m,4H), 1.4-1.0 (m, 3H, CHMe).

EXAMPLE 21(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[[N-[4-(2,2,2-trifluoroethoxy)benzoyl]-N-(2-hydroxyethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR65##

Following the procedure described in example 3, but using the compoundobtained in example 20, the title compound was prepared in a similaryield.

mp: 110°-112° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.28 (s, 1H, triazole), 8.0-7.3 (m, 4H,triazole, arom), 7.02 (d, J=8.5Hz, 2H, arom), 6.9-6.5 (m, 2H, arom),5.1-3.5 (m), 4.41 (q, J=8.1Hz, 2H, CH₂ CF₃), 1.4-1.0 (m, 3H, CHMe);

Analysis Calcd. for C₂₃ H₂₃ F₅ N₄ O₄ : C 53.70; H 4.51; N 10.89. Found:C 53.70; H 4.47; N 10.69.

EXAMPLE 22(5R*,6R*)-6-[2,4-Dichlorophenyl]-5-methyl-2-hydroxy-4-[4-(2,2,3,3-tetrafluoropropoxy)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholine##STR66##

Following the Method A described in example 13, but using the compoundobtained in example 6, the title compound was obtained.

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.85 (s, 1H, triazole), 7.8-7.0 (m, 8H,arom), 6.09 (tt, J=4.8Hz, J=53Hz, 1H, CF₂ H), 5.9-5.2 (m, 2H), 5.2-4.5(m, 2H), 4.41 (dt, J=12Hz, J=1.4Hz, 2H, CH₂ CF₂), 4.0-3.0 (m, 2H), 1.10(d, J=7Hz, 3H, CHMe);

Analysis Calcd. for C₂₄ H₂₂ Cl₂ F₃ N₄ O₄ : C 51.63; H 3.97; N 10.03Found: C 51.55; H 4.24; N 10.21.

EXAMPLE 23(5R*,6R*)-6-[2,4-Dichlorophenyl]-5-methyl-2-hydroxy-4-[4-(trifluoromethyl)-benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholine##STR67##

Following the Method A described in example 13, but using the compoundobtained in example 10, the title compound was prepared.

mp: 199°-200° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.83 (s, 1H, triazole), 7.8-7.0 (m, 8H,triazole, arom), 6.3-5.6 (m), 5.6-5.2 (m), 5.1-4.6 (m), 3.9-3.3 (m, 2H,OCHCH₂), 1.11 (d, J=7.2Hz, 3H, CHMe);

Analysis Calcd. for C₂₂ H₁₉ C₁₂ F₃ N₄ O₃.1/2 AcOEt: C 51.53; H 4.14; N10.02.

Found: C 52.33; H 4.19; N 10.02.

EXAMPLE 24(SR*,6R*)-6-[2,4-Dichlorophenyl]-5-methyl-2-(1H-1,2,4-triazol-1-yl)-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholine##STR68##

To a cooled (0° C.) solution containing the compound of example 23 (300mg, 0.58 mmol), triphenylphosphine (305 mg, 1.16 mmol, 2 eq), and1,2,4-triazole (80.4 mg, 1.16 mmol, 2 eq) in dry THF (10 mL) it wasadded diethylazadicarboxylate (203 mg, 0.183 mL, 1.16 mmol, 2 eq). Themixture was stirred at 0° C. during 30 min and at room temperatureduring 1 h. The volatiles were then removed in vacuo and the residue waschromatographed on silica gel (EtOAc) to afford the title compound aswhite solid.

mp: 191°-201° C.;

¹ H NMR (80 MHz, MeOH-d4) δ (TMS): 8.74 (s, 1H, triazole), 8.05 (s, 1H,triazole), 7.83 (br s, 5H, triazole, arom), 7.6-7.3 (m, 3H, triazole,arom), 7.18 (br d, J=8.9Hz, 1H, arom), 6.5-6.1 (m, 1H, OCHTr), 5.29 (s,2H), 5.3-5.0 (m, 1H, CHMe), 4.18 (br s, 2H), 1.26 (d, J=6.6Hz, 3H,CHMe);

Analysis Calcd. for C₂₄ H₂₀ C₁₂ F₃ N₇ O₂ : C 50.90; H 3.56; N 17.31.Found: C 50.66; H 3.43; N 16.98.

EXAMPLE 25(5R*,6R*)-6-[2,4-Dichlorophenyl]-5-methyl-2-fluoro-4-[4-(trifluoromethyl)-benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholine##STR69##

To a cooled (-10° C.) solution containing the compound of example 23(360 mg, 0.70 mmol) in CH₂ C₁₂ (4 mL) it was added a solution containingdiethylaminosulfur trifluoride (DAST) (124 mg, 0.102 mL, 0.77 mmol, 1.1eq) in CH₂ Cl₂ (1 mL) and the reaction mixture was stirred for 1 h. Thereaction was quenched by the addition of water (10 mL) and more CH₂ Cl₂was added. The organic phase was separated and washed with 5% NahCO₃aqueous solution and brine, dried over anhydrous Na₂ SO₄, the dryingagent was then filtered and the resulting filtrate was concentrated toan oil that was purified by silica gel chromatography (EtOAc:Hex 2:1) toafford the title product as a white solid in poor yield.

mp: 151°-156° C.;

¹ H NMR (80 MHz, MeOH-d4) δ (TMS): 8.34 (s, 1H, triazole), 8.0-7.7 (m,triazole, arom), 7.6-7.1 (m, arom), 6.9-6.5 (m), 6.4-5.8 (m), 5.7-4.8(m), 4.2-3.3 (m), 1.4-0.8 (m, 3H, CHMe);

Analysis Calcd. for C₂₂ H₁₈ Cl₂ F₄ N₄ O₂ : C 51.08; H 3.51; N 10.83.Found: C 51.46; H 3.63; N 10.70.

EXAMPLE 26(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine,benzyl ester ##STR70##

Following the procedure described in example 1, but starting from thecompound obtained in reference example 8, the title compound wasobtained as a white solid.

mp: 175°-181° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.0-7.0 (complex signal, 15H, triazole,arom), 6.9-6.5 (m, 2H, arom), 5.7-5.0 (m), 4.85 (br s), 4.7-4.2 (m),1.2-0.9 (m, 3H, CHMe);

Analysis Calcd. for C₂₉ H₂₅ F₅ N₄ O₄ : C 59.18; H 4.28; N 9.52. Found: C59.93; H 4.59; N 9.20.

EXAMPLE 27(2R*,3R*)-N-[3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine,ethyl ester ##STR71##

Following the procedure described in example 1, but starting from thecompound obtained in reference example 9, the title compound wasobtained.

mp: 170°-178° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.04 (s, 1H, triazole), 7.9-7.3 (m, 8H,triazole, arom), 7.2-6.9 (m, 1H, arom), 6.3-5.7 (m), 5.4-5.2 (m), 5.03(s), 5.1-4.8 (m), 4.57 (s), 4.4-4.1 (m), 4.08 (q, J=7.1Hz, OCH? CH3),1.35 (t, J=7.1Hz, OCH₂ CH₃), 1.2-0.9 (m, 3H, CHMe).

Analysis Calcd. for C₂₄ H₂₃ Cl₂ F₃ N₄ O₄ : C 51.53; H 4.14; N 10.02.Found: C 51.83; H 4.22; N 9.93.

EXAMPLE 28 (2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine##STR72##

To a solution of (2R*,3R*)-2-(2,4-difluorophenyl)-3-(N-benzyloxycarbonylmethylamino-N-4-trifluoromethylbenzoylamino)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(3.4 g, 5.7 mmol) (obtained in example 26) in ethanol (90 mL) was added10% palladium on charcoal (0.8 g) and the mixture was hydrogenated (1atm) during 2 h. The mixture was filtered and the solvent removed invacuo to afford the title product as a white solid (2.81 g, 99%).

mp: 182°-183° C.;

¹ H NMR (80 MHz, MeOH-d4) δ (TMS): 8.24 and 8.18 (s, 1H, triazole),8.0-7.6 (m, triazole, arom), 7.5-7.1 (m, 1H, arom), 7.0-6.6 (m, 2H,arom), 5.9-5.6 (m), 5.10 (br s), 4.97 (s), 4.76 (s), 4.60 (s), 4.50 (s),4.32 (s), 1.11 (d, J=6.8Hz, 3H, CHMe);

Analysis Calcd. for C₂₂ H₁₉ F₅ N₄ O₄ : C 53.02; H 3.84; N 11.24. Found:C 53.71; H 3.91; N 11.38.

EXAMPLE 29(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone##STR73##

Method A: A cooled (-10° C.) solution containing(2R*,3R*)-N-[3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine(12.24 g, 24.55 mmol) (obtained in example 28) in pyridine was treatedwith trifluoroacetic anhydride (5.2 mL, 36.83 mmol, 1.5 eq). The mixturewas stirred during 15 min at -10° C. and during 2 h at 0° C. Theresulting red solution was then quenched by the addition of pH 7phosphate buffer, concentrated in vacuo and partitioned between waterand CHCl₃. The aqueous phase was discarded and the organic layer waswashed with 5% aqueous NaHCO₃ and brine, then it was dried overanhydrous Na₂ SO₄, the drying agent was filtered and the filtrate wasconcentrated to a reddish solid which was flash-chromatographed(EtOAc:Hex 2:1) to a white solid (10.0 g, 85%).

mp: 184°-186° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.0-7.3 (m, 7H, triazole, arom),7.0-6.7 (m, 2H, arom), 4.79 (s), 4.4-4.0 (m), 1.20 and 1.11 (d, J=7Hz,3H, CHMe).

MS (EI): M⁺ +1=480

Analysis Calcd. for C₂₂ H₁₇ F₅ N₄ O₃ : C 55.01; H 3.57; N 11.66. Found:C 55.10; H 3.49; N 11.51.

Method B: A solution containing(2R*,3R*)-N-[3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine(122 mg, 0.24 mmol) (obtained in example 28) in DMF (5 mL) was treatedwith DCC (60 mg, 0.29 mmol) and the mixture stirred during 20 h. Theprecipitated urea was filtered and the filtrate was partitioned betweenwater and EtOAc. The aqueous phase was separated and the organic phasewas washed with 5% NaHCO₃ aqueous solution and brine, then dried overanhydrous Na₂ SO₄, the drying agent was filtered and the filtrate wasconcentrated to afford the title compound in quantitative yield. Thisprocedure, however, yielded trace amounts of dicyclohexylurea difficultto remove from the desired product.

Method C: a suspension of(2R*,3R*)-2-[2,4-difluorophenyl]-3-[[N-[4-(trifluoromethyl)benzoyl]-N-(2-hydroxyethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (100 mg, 0.2 mmol) (obtained as describedin example 3), and 1 g of silver carbonate suspended in celite inbenzene (10 mL) was heated under reflux for 4 h. The mixture wasconcentrated and the product was isolated by flash chromatography(EtOAc: Hex 3:1) to give the title compound of the example as a whitesolid (23 mg, yield: 24%).

EXAMPLE 30(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethoxy)benzoyl]glycine,benzyl ester ##STR74##

Following the procedure described in example 1, but starting from thecompound obtained in reference example 8 and using4-(trifluoromethoxy)benzoyl chloride instead of4-(trifluoromethyl)benzoyl chloride, the title compound was obtained asa white solid.

mp: 153°-155° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.76 (s, 1H, triazole), 7.6-7.0 (m,triazole, arom), 6.9-6.5 (m, 2H, arom), 5.3-4.2 (m, 7H), 1.05 (d,J=6.2Hz, 3H, CHMe).

Analysis Calcd. for C₂₉ H₂₅ F₅ N₄ O₅ : C 57.62; H 4.17; N 9.27. Found: C57.74; H 3.97; N 9.06.

EXAMPLE 31 (UR-9727)(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethoxy)benzoyl]glycine##STR75##

Following the procedure described in example 28, but starting from thecompound obtained in example 30, the title compound was obtained as awhite solid.

mp: 99°-105° C.;

¹ H NMR (80 MHz, MeOH-d₄) δ (TMS): 8.19 (s, 1H, triazole), 7.8-7.0 (m,6H, triazole, arom), 7.0-6.6 (m, 2H, arom), 5.2-4.2 (m, 5H), 1.10 (d,J=6.8Hz, 3H, CHMe).

Analysis Calcd. for C₂₂ H₁₉ F₅ N₄ O₅ : C 51.37; H 3.72; N 10.89. Found:C 51.57; H 3.53; N 10.36.

EXAMPLE 32(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(trifluoromethoxy)benzoyl]-6-(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone##STR76##

Following the procedure described in method A of example 29, butstarting from the compound obtained in example 31, the title compoundwas obtained as a white solid.

mp: 180°-181° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.90 (s, 1H, triazole), 7.72 (s, 1H,triazole), 7.7-7.3 (m, 5H, arom), 7.1-6.7 (m, 2H, arom), 5.0-4.6 (m, 1H,CHMe), 4.81 (AB quartet, Δv=0.133, J=14.9Hz, 2H, CH₂ Tr), 4.33 (s), 4.09(s), 1.11 (d, J=6.9Hz, 3H, CHMe).

Analysis Calcd. for C₂₂ H₁₇ F₅ N₄ O₄ : C 53.23; H 3.45; N 11.29. Found:C 53.10; H 3.33; N 11.02.

EXAMPLE 33(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(2,2,2-trifluoroethoxy)benzoyl]glycine,benzyl ester ##STR77##

Following the procedure described in example 1, but starting from thecompound obtained in reference example 8 and using4-(2,2,2-trifluoroethoxy)benzoyl chloride instead of4-(trifluoromethyl)benzoyl chloride, the title compound was obtained asa white solid.

mp: 135°-136° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.76 (s, 1H, triazole), 7.6-7.1 (m,triazole, arom), 7.0-6.6 (m, arom), 5.4-4.8 (m), 4.6-4.1 (m), 1.05 (d,J=6.8Hz, 3H, CHMe).

Analysis Calcd. for C30H27F₅ N4O₅ : C 58.25; H 4.40; N 9.06. Found: C58.45; H 4.28; N 8.87.

EXAMPLE 34(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(2,2,2-trifluoroethoxy)benzoyl]glycine##STR78##

Following the procedure described in example 28, but starting from thecompound obtained in example 33, the title compound was obtained as awhite solid.

mp: 168°-177° C.;

¹ H NMR (80 MHz, MeOH-d₄) δ (TMS): 8.19 (s, 1H, triazole), 7.7-7.4 (m,3H, triazole, arom), 7.3-7.0 (m, 3H, arom), 7.0-6.6 (m, 2H, arom),5.1-4.2 (m), 1.09 (d, J=6.8Hz, 3H, CHMe).

Analysis Calcd. for C₂₃ H₂₁ F₅ N₄ O₅ : C 52.28; H 4.01; N 10.60. Found:C 52.09; H 3.98; N 10.53.

EXAMPLE 35(SR*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(2,2,2-trifluoroethoxy)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone##STR79##

Following the procedure described in method A of example 29, butstarting from the compound obtained in example 34, the title compoundwas obtained as a white solid.

mp: 162°-163° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.86 (s, 1H, triazole), 7.70 (s, 1H,triazole), 7.50 (d, J=8.7Hz, 2H, arom), 7.4-7.2 (m, 1H, arom), 7.06 (d,J=8.7Hz, 2H, arom), 6.9-6.7 (m, 2H, arom), 4.81 (AB quartet, Δv 0.171,J- 14.9Hz, 2H, CH₂ Tr), 5.0-4.6 (m, 1H, CHMe), 4.44 (q, J=8Hz, 2H, CH₂CF₃), 4.36 (s), 4.11 (s), 1.11 (d, J=7Hz, 3H, CHMe);

Analysis Calcd. for C₂₃ H₁₉ F₅ N₄ O₄ : C 54.12; H 3.75; N 10.98. Found:C 54.19; H 3.65; N 10.76.

EXAMPLE 36(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(2,2,3,3-tetrafluoropropoxy)benzoyl]glycine,benzyl ester ##STR80##

Following the procedure described in example 1, but starting from thecompound obtained in reference example 8 and using4-(2,2,3,3-tetrafluoropropoxy)benzoyl chloride (obtained according topatent EP 472392) instead of 4-(trifluoromethyl)benzoyl chloride, thetitle compound was obtained as a white solid.

mp: 133°-134° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.75 (s, 1H, triazole), 7.5-7.1 (m,triazole, arom), 7.34 (s, 5H, phenyl), 7.0-6.5 (m, arom), 6.06 (tt,J=4.7Hz, J=53Hz, 1H, CF₂ H), 5.3-4.1 (m), 1.04 (d, J=6.8Hz, 3H, CHMe).

Analysis Calcd. for C₃₁ H₂₈ F₆ N₄ O₅ : C 57.23; H 4.34; N 8.61. Found: C57.29; H 4.35; N 8.50.

EXAMPLE 37(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(2,2,3,3-tetrafluoropropoxy)benzoyl]glycine##STR81##

Following the procedure described in example 28, but starting from thecompound obtained in example 36, the title compound was obtained as awhite solid.

mp: 183°-184° C.;

¹ H NMR (80 MHz, MeOH-d₄) δ (TMS): 8.18 (s, 1H, triazole), 7.66 (s, 1H,triazole), 7.6-7.4 (m, 2H, arom), 7.3-6.6 (m, 5H, arom), 6.34 (m, 1H,CF₂ H), 5.2-4.2 (m), 1.09 (d, J=6.7Hz, 3H, CHMe).

Analysis Calcd. for C₂₄ H₂₂ F₆ N₄ O₅ : C 51.43; H 3.96; N 9.00. Found: C51.52; H 3.87; N 9.89.

EXAMPLE 38(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(2,2,3,3-tetrafluoropropoxy)-benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone ##STR82##

Following the procedure described in method A of example 29, butstarting from the compound obtained in example 37, the title compoundwas obtained as a white solid.

mp: 78°-83° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.92 (s, 1H, triazole), 7.71 (s, 1H,triazole), 7.6-6.8 (m, 7H, arom), 6.07 (tt, J=4.6Hz, J=53Hz, 1H, CF₂ H),5.1-4.0 (m), 1.11 (d, J=7Hz, 3H, CHMe).

Analysis Calcd. for C₂₄ H₂₀ F₆ N₄ O₄ : C 53.14; H 3.72; N 10.33. Found:C 53.10; H 3.79; N 9.75.

EXAMPLE 39(2R*,3R*)-N-[3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine,benzyl ester ##STR83##

Following the procedure described in example 1, but using the compoundobtained in reference example 10, the title compound was obtained as awhite solid.

182°-183° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.86 (s, 1H, triazole), 7.75 (s, 1H,triazole), 7.38 (s, 5H, benzyl), 7.7-7.0 (m, 7H, arom), 6.2-5.7 (m),5.27 (s, 2H, CH₂ Ph), 5.3-4.7 (m), 4.64 (s, 1/2 CH₂ CO), 4.30 (s, 1/2CH₂ CO), 1.03 and 1.00 (d, J=7Hz, 3H, CHMe);

Analysis Calcd. for C₂₉ H₂₅ Cl₂ F₃ N₄ O₄ : C 56.05; H 4.05; N 9.02.Found: C 56.02; H 4.00; N 9.04.

EXAMPLE 40(2R*,3R*)-N-[3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine ##STR84##

Following the procedure described in example 28, but starting from thecompound obtained in example 39, the title compound was obtained as awhite solid.

mp: 183°-189° C.;

¹ H NMR (80 MHz, MeOH-d₄) δ (TMS): 8.26 and 8.17 (s, 1H, triazole),8.0-7.6 (m, triazole, arom), 7.5-7.1 (m, arom), 6.4-6.1 (m), 5.9-5.5(m), 5.05 (br s), 4.54 (s), 4.25 (s), 1.05 (d, J=6.9Hz, 3H, CHMe);

Analysis Calcd. for C₂₂ H₁₉ Cl₂ F₃ N₄ O₄ : C 49.73; H 3.60; N 10.54.Found: C 49.46; H 3.56; N 10.40.

EXAMPLE 41(5R*,6R*)-6-[2,4-Dichlorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone##STR85##

Following the procedure described in method A of example 29, butstarting from the compound obtained in example 40, the title compoundwas obtained as a white solid.

mp: 184°-187° C.;

¹ H NMR (80 MHz, CDCl₃) 15 (TMS): 7.9-7.3 (m, triazole, arom), 7.3-7.1(m, 1H, arom), 5.5-4.9 (m, 1H, CHMe), 5.01 (AB quartet, Δv=0.444,J=14.8Hz, 2H, CH₂ Tr), 4.29 (s), 4.05 (s), 1.08 (d, J=6.8Hz, 3H, CHMe);

Analysis Calcd. for C₂₂ H₁₇ Cl₂ F₃ N₄ O₃ : C 51.48; H 3.34; N 10.91.Found: C 51.76; H 3.40; N 10.75.

EXAMPLE 42(2R*,3R*)-N-[3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(2,2,3,3-tetrafluoropropoxy)benzoyl]glycine,benzyl ester ##STR86##

Following the procedure described in example 1, but starting from thecompound obtained in reference example 10 and using4-(2,2,3,3-tetrafluoropropoxy)benzoyl chloride (obtained according topatent EP 472392) instead of 4-(trifluoromethyl)benzoyl chloride, thetitle compound was obtained as a white solid.

mp: 69°-74° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.74 (s, 1H, triazole), 7.6-6.7 (m,triazole, arom), 6.06 (tt, J=4.6Hz, J=53Hz, 1H, CF₂ H), 5.3-4.1 (m, 7H),1.00 (d, J=6.9 Hz, 3H, CHMe).

Analysis Calcd. for C₃₁ H₂₈ Cl₂ F₄ N₄ O₅ : C 54.48; H 4.13; N 8.20.Found: C 54.21; H 4.17;N8.11.

EXAMPLE 43(2R*,3R*)-N-[3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(2,2,3,3-tetrafluoropropoxy)benzoyl]glycine##STR87##

Following the procedure described in example 28, but starting from thecompound obtained in example 42, the title compound was obtained as awhite solid.

mp: 192°-193° C.;

¹ H NMR (80 MHz, MeOH-d₄) δ (TMS): 8.15 (s, 1H, triazole), 7.67 (s, 1H,triazole), 7.6-7.0 (m, arom), 6.34 (tt, J=53Hz, J=4.8Hz, 1H, CF₂ H),6.4-6.0 (m), 5.8-5.5 (m), 5.31 (q, J=6.8Hz, 1H, CHMe), 4.98 (AB quartet,Δv=0.103, J=15Hz, 2H, CH₂ Tr), 4.52 (s), 4.38 (s), 1.04 (d, J=6.8Hz, 3H,CHMe);

Analysis Calcd. for C₂₄ H₂₂ Cl₂ F₄ N₄ O₅ : C 48.58; H 3.74; N 9.44.Found: C 48.73; H 3.76; N 9.35.

EXAMPLE 44(SR*,6R*)-6-[2,4-Dichlorophenyl]-5-methyl-4-[4-(2,2,3,3-tetrafluoropropoxy)-benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone##STR88##

Following the procedure described in method A of example 29, butstarting from the compound obtained in example 43, the title compoundwas obtained as a white solid.

mp: 88°-94° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.82 (s, 1H, triazole), 7.70 (s, 1H,triazole), 7.6-7.4 (m, arom), 7.3-6.9 (m, arom), 6.06 (tt, J=53Hz,J=4.5Hz, 1H, CF₂ H), 5.23 (br s), 4.80 (s), 4.44 (br t, J=11.8Hz, 2H,CF₂ CH₂), 4.33 (s), 4.10 (s), 1.08 (d, J=7Hz, 3H, CHMe);

Analysis Calcd. for C₂₄ H₂₀ Cl₂ F₄ N₄ O₄ : C 50.10; H 3.50; N 9.74.Found: C 50.14; H 3.56; N 9.50.

EXAMPLE 45(2R*,3R*)-N-[3-[4-(Trifluoromethyl)phenyl]-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine,benzyl ester ##STR89##

Following the procedure described in example 1, but starting from thecompound obtained in reference example 21, the title compound wasobtained as a white solid.

mp: 139°-140° C. (ether);

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.77 (s, 1H, triazole), 7.64 (s, 1H,triazole), 7.51 (br s, arom), 7.4-7.2 (m, arom), 5.5-5.1 (m, 1H, CHMe),5.09 (s, 2H, CH₂ Ph), 4.98 (br s, 2H, CH₂ Tr), 4.31 (s, 2H, CH₂ CO),1.03 (d, J=7Hz, 3H, CHMe).

EXAMPLE 46(2R*,3R*)-N-[3-[4-(Trifluoromethyl)phenyl]-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluorornethyl)benzoyl]glycine##STR90##

Following the procedure described in example 28, but starting from thecompound obtained in example 45, the title compound was obtained as awhite solid.

mp: 201°-204° C.;

¹ H NMR (80 MHz, MeOH-d₄) δ (TMS): 8.16 (s, 1H, triazole), 7.9-7.5 (m,9H, triazole, arom), 5.04 (s), 4.5-4.0 (m), 1.20 and 1.08 (d, J=7Hz, 3H,CHMe).

Analysis Calcd. for C₂₃ H₂₀ F₆ N₄ O₄ : C 52.08; H 3.80; N 10.56. Found:C 52.78; H 3.78; N 10.65.

EXAMPLE 47(5R*,6R*)-6-[4-(Trifluoromethyl)phenyl]-5-methyl-4-[4-(trifluoromethyl)-benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone##STR91##

Following the procedure described in method A of example 29, butstarting from the compound obtained in example 46, the title compoundwas obtained as a white solid.

mp: 189°-190° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.9-7.3 (m, 10H, triazole, arom), 4.73(s), 4.5-4.0 (m), 1.10 (d, J=6.9Hz, 3H, CHMe).

Analysis Calcd. for C₂₃ H₁₈ F₆ N₄ O₃ : C 53.91; H 3.54; N 10.93. Found:C 54.23; H 3.71; N 10.76.

EXAMPLE 48(2R*,3R*)-2-[2,4-Dichlorophenyl-3-[[N-[4-(trifluoromethyl)benzoyl]-N-(2-(1H-1,2,4-triazol-1-yl)ethyl)]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol##STR92##

Following the acylation procedure described in example 1, but startingfrom the product obtained in reference example 27, the title product wasobtained in a similar yield as a white solid.

mp: 91°-99° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.13 (s, 1H, triazole), 7.99 (s, 1H,triazole), 7.9-7.0 (m, triazole, arom), 5.5-5.0 (m), 4.9-4.1 (m),0.9-0.6 (m, 3H, CHMe);

Analysis Calcd. for C₂₄ H₂₂ Cl₂ F₃ N₇ O₂ : C 50.72; H 3.90; N 17.25.Found: C 51.14; H 4.43; N 16.88.

EXAMPLE 49 (2R,3R)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine,benzyl ester ##STR93##

Following a procedure identical to that described in Example 26, butusing the compound obtained in reference example 22, the title compoundwas prepared as a white solid. The NMR spectrum of the compound thusprepared matched with that of the compound obtained in example 26.

mp: 87°-89° C.;

[α]_(D) -63° (c=1, MeOH).

EXAMPLE 50(2R,3R)-N-[3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine,benzyl ester ##STR94##

Following a procedure identical to that described in example 39, butusing the compound obtained in reference example 23, the title compoundwas prepared as a white solid. The NMR spectrum of the compound thusprepared was identical to that of the compound obtained in example 39.

mp: 82°-86° C.;

[α]_(D) -76.3° (c=1, MeOH).

EXAMPLE 51(2R,3R)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine##STR95##

Following a procedure identical to that described in example 28, butusing the compound obtained in example 49, the title compound wasprepared as a white solid. The NMR spectrum of the compound thusprepared was identical to that of the compound obtained in example 28.

mp: 132°-135° C.;

[α]_(D) -73.9° (c=1, MeOH).

EXAMPLE 52(2R,3R)-N-[3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycine##STR96##

Following a procedure identical to that described in example 40, butusing the compound obtained in example 50, the title compound wasprepared as a white solid. The NMR spectrum of the compound thusobtained was identical to that of the compound prepared in example 40.

mp: 140°-142° C.;

[α]_(D) -89.0° (c=1, MeOH).

EXAMPLE 53 (5R,6R)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(trifluoromethyl)1,2,4-triazol-1-yl)methyl]-2-morpholinone ##STR97##

Following a procedure identical to that described in example 29, butusing the compound obtained in example 51, the title compound wasprepared as a white solid. The NMR spectrum of the compound thusprepared was identical to that of the compound obtained in example 29.

mp: 189°-190° C.;

[α]_(D) -26.4° (c=1, MeOH).

EXAMPLE 54(5R,6R)-6-[2,4-Dichlorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-124-triazol-1-yl)methyl]-2-morpholinone ##STR98##

Following a procedure identical to that described in example 41, butusing the compound obtained in example 52, the title compound wasprepared as a white solid. The NMR spectrum of the compound thusprepared was identical to that of the compound obtained in example 41.

mp: 138°-139° C.;

[α]_(D) -54.1° (c=1, MeOH)

EXAMPLE 55(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]-DL-alanine,benzyl ester ##STR99##

Following the procedure described in example 1, but starting from thecompound obtained in reference example 24 and stirring the reaction atreflux for 20 h, the title compound was prepared as a yellowish solid in32% yield.

mp: 70°-76° C.;

¹ H NMR (80 MHz, CD₃ OD) δ (TMS): 7.91 (s), 7.86 (s), 7.81 (s), 7.63(s), 7.5-7.0 (complex signal), 6.71 (br tr, J=8.3Hz, arom), 5.31 (d,J=14 Hz, 1H, CH(H)), 5,27 (s, 2H, CH₂ Ph), 5.06 (q, J=6.8Hz, 1H, CHMe),4,58 (q, J=7.1Hz, 1H, CHMe), 4.15 (d, J=14Hz, 1H, CH(H)), 1.69 (d,J=7Hz, 3/2H, CHMe), 1.16 (d, J=7Hz, 3/2 H, CHMe).

Analysis Calcd. for C₃₀ H₂₇ F₅ N₄ O₄ : C 59.80; H 4.52; N 9.30. Found: C59.92; H 4.51; N 9.17.

EXAMPLE 56 (2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]-DL-alanine##STR100##

Following the hydrogenation procedure described in example 28, butstarting from the compound obtained in example 55, the title compoundwas obtained in 80% yield.

mp: 219°-221° C.;

¹ H NMR (80 MHz, CDCl₃ +MeOH-d₄) δ (TMS): 8.09 (s, 1H, triazole),7.9-7.5 (m, triazole, arom), 7.5-7.1 (m, 1H, arom), 7.0-6.5 (m, 2H,arom), 5.6 (d, J=14Hz, 1H, CH(H)), 5.93 (q, J=7Hz, 1H, CHMe), 4.65 (brq, J=7Hz, 1H, CHMe), 4.41 (d, J=14Hz, 1H, CH(H)), 1.69 (d, J=7Hz, 3/2H,CHMe), 1.18 (d, J=7Hz, 3/2H, CHMe).

Analysis Calcd. for C₂₃ H₂₁ F₅ N₄ O₄ : C 53.91; H 4.13; N 10.93. Found:C 54.05; H 4.07; N 11.01.

EXAMPLE 57(3RS,5R*,6R*)-6-[2,4-Difluorophenyl]-3,5-dimethyl-4-[4-(trifluoromethyl)-benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone##STR101##

Following the procedure described in method A of example 29, butstarting from the compound obtained in example 56, the title compoundwas obtained in 15% yield as a white solid.

mp: 176°-180° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.0-7.35 (m, 7H, triazole, arom),7.5-7.0 (m, H, arom), 7.0-6.5 (m, 2H, arom), 5.6-4.4 (complex signal),1.7-1.5 (m, CHMe.), 1.25 (d, J=7Hz, CHMe), 1.04 (d, J=7Hz, CHMe).

Analysis Calcd. for C₂₃ H₁₉ F₅ N4O₃ : C 55.87; H 3.87; N 11.33 Found: C55.44; H 4.04; N 11.44.

EXAMPLE 58(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[methanesulphonyl]glycine,benzyl ester ##STR102##

Following the procedure described in example 1, but starting from thecompound obtained in reference example 8 and using methanesulphonylchloride instead of 4-(trifluoromethyl)benzoyl chloride, the titlecompound was obtained as a white solid.

mp: 56°-59° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.46 (br s, 2H, triazole), 7.5-7.1 (m,1H, arom), 7.36 (s, 5H, benzyl), 7.0-6.5 (m, 2H, arom), 5.30 (s), 5.15(d, J=14.3Hz, 1H, CH(H)), 4.85 (d, J=14.3Hz, 1H, CH(H)), 4.52 (br s, 2H,CH₂), 4.6-4.3 (m, 1H, CHMe), 3.10 (s, 3H, SO₂ Me), 1.03 (d, J=7Hz, 3H,CHMe).

EXAMPLE 59(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl-N-[methanesulphonyl]glycine##STR103##

Following the procedure described in example 28, but starting from thecompound obtained in example 58, the title compound was obtained as awhite solid.

mp: 165°-173° C.;

¹ H NMR (80 MHz, DMSO-d₆) δ (TMS): 8.21 (br s, 1H, triazole), 7.68 (brs, 1H, triazole), 7.4-6.8, complex signal, 3H, arom), 4.98 (AB q,Δv=0.34, J=14.3 Hz, 2H, TrCH2), 4.47 (q, J=7Hz, 1H, CHMe), 4.13 (s, 2H,CH₂ CO₂ H), 3.10 (s, 3H, SO₂ Me), 0.91 (d, J=7Hz, 3H, Me).

Analysis Calcd. for C₁₅ H₁₈ F₂ N₄ O₅ S: C 44.55, H 4.49, N 13.85, S7.93. Found: C 43.01, H 4.61, N 12.41, S 7.50.

EXAMPLE 60 (5R *,6R *)-6-[2,4-Difluorophenyl]-5-methyl-4-(methanesulphonyl)-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone##STR104##

Following the procedure described in method A of example 29, butstarting from the compound obtained in example 59, the title compoundwas obtained as a white solid.

mp: 180°-181° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 7.83 (s, 1H, triazole), 7.70 (s, 1H,triazole), 7.5-7.1 (m, 1H, arom), 7.1-6.7 (m, 2H, arom), 5.0-4.7 (m, 1H,CHMe), 4.92 (AB quartet, 2H, CH₂ Tr), 4.68 (d, J=17Hz, 1H, CH(H)), 4.02(d, J=17Hz, 1H, CH(H)) 3.05 (s, 3H, SO₂ Me), 1.10 (d, J=7Hz, 3H, CHMe).

Analysis Calcd. for C₁₅ H₁₆ F₂ N₄ O₄ S: C 46.63; H 4.17; N 14.50; S8.30. Found: C 46.36; H 4.25; N 14.24; S 7.89.

EXAMPLE 61(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[2-fluoro-4-(trifluoromethyl)benzoyl]glycine,benzyl ester ##STR105##

Following the procedure described in example 1, but starting from thecompound obtained in reference example 8 and using2-fluoro-4-(trifluoromethyl)benzoyl chloride instead of4-(trifluoromethyl)benzoyl chloride, the title compound was obtained asa white solid.

mp: 70°-73° C.;

¹ H NMR (80 MHz, CD₃ OD) δ (TMS): 7.80 (s), 7.76 (s), 7.7-7.0 (complexsignal, arom H), 7.0-6.5 (complex signal, 2H, arom), 5.60 (q, J=7 Hz,1H, CHMe), 5,27 (s), 5.15 (s), 5.03 (s), 4.93 (s), 4.7-4.5 (m), 4.3-4.2(m), 1.07 and 1.02 (two d, J=7Hz, 3H, Me).

Analysis Calcd. for C₂₉ H₂₄ F₆ N₄ O₄ : C 57.43; H 3.99; N 9.24. Found: C57.42; H 4.02; N 9.06.

EXAMPLE 62(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[2-fluoro-4-(trifluoromethyl)benzoyl]glycine##STR106##

Following the hydrogenation procedure described in example 28, butstarting from the compound obtained in example 61, the title compoundwas obtained in 100% yield.

mp: 191°-192° C.;

¹ H NMR (80 MHz, MeOH-d₄) δ (TMS): 8.21 (d, J=3.7 Hz, 1H, arom), 7.9-7.7(m, 4H, triazole, arom), 7.5-7.1 (m, 1H, arom), 7.1-6.5 (m, 2H, arom),5.72 (q, J=7Hz, 1H, CHMe), 5.07 (AB q, 2H, CH₂ Tr), 4.49 (s), 4.28 (s),1.11 and 1.06 (d, J=7Hz, 3Me).

Analysis Calcd. for C₂₂ H₁₈ F₆ N₄ O₄ : C 51.91; H 3.51; N 10.85. Found:C 51.80; H 3.69; N 10.13.

EXAMPLE 63(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-4-[2-fluoro-4-(trifluoromethyl)-benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone##STR107##

Following the cyclization procedure described in example 29, butstarting from the compound obtained in example 62, the title compoundwas obtained in 82 % yield as a white solid.

mp: 191°-192° C.;

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.0-7.35 (m, 6H, triazole, arom),7.2-6.6 (m, 2H, arom), 5.84 (br q, J=7 Hz, 1H, CHMe), 5.1-4.3 (complexsignal, 3H), 4.20 (s), 1.13 and 1.05 (d, J=7Hz, 3H, Me).

Analysis Calcd. for C₂₂ H₁₆ F₆ N₄ O₃ : C 53.02; H 3.24; N 11.24 Found: C52.99; H 3.31; N 11.24.

EXAMPLE 64(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholine##STR108##

A solution containing(2R*,3R*)-2-[2,4-difluorophenyl]-3-[N-(2-hydroxyethyl)-N-[4-(trifluoromethyl)benzoyl]amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol(500 mg, 1.03 mmol, obtained in example 3) in THF was treated withdiethylazadicarboxylate (262 mg, 1.5 eq) and triphenylphosphine (393 mg,1.5 eq) at room temperature for 24 h. The volatiles were removed invacuo and the orange oily residue was purified by flash chromatographyto afford the title compound as a colorless wax (209 mg, 45 % yield).

¹ H NMR (80 MHz, CDCl₃) δ (TMS): 8.0-7.1 (m, 6H, triazole, arom),7.1-6.6 (m, 2H, arom), 5.50 (br q, J=7 Hz, 1H, CHMe), 5.32 (br s), 5.13(br s), 4.9-3.3 (complex signal, 3H), 1.12 (br d, J=7Hz, 3H, Me). MS(CI, CH₄) 467 (M+1)

EXAMPLE 65(2R*,3R*)-N-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]-N-[4-(trifluoromethyl)benzoyl]glycinamide##STR109##

To a solution of(5R*,6R*)-6-[2,4-difluorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinone(0.5 g, 1 mmol) (obtained in example 29) in acetone (15 mL) was addeddropwise 30% ammonium hydroxide (5 mL) and the mixture was stirred atroom temperature during 1 h. The volatiles were removed under reducedpressure and the residue was partitioned between 1N NaHCO₃ andchloroform. The organic phase was separated, dried over anhydrous sodiumsulfate, the drying agent was filtered and the solvent removed in vacuoto afford the title product as a white solid (0.38 g, 80%).

mp: 147°-148° C.;

¹ H NMR (80 MHz, MeOH-d4) δ (TMS): 7.86 (s, triazole), 7.8-7.5 (m,triazole, arom), 7.5-7.0 (m, 1H, arom), 6.9-6.5 (m, 2H, arom), 6.21 (brs, 2H, NH2), 5.8-4.7 (complex signal), 4.65 (br q, J=7Hz, CHMe), 4.49(br s), 4.35 (s), 4.17 (s), 1.08 (br d, J=7Hz, 3H, CHMe);

Analysis Calcd. for C₂₂ H₂₀ F₅ N₅ O₃ : C 53.12; H 4.05; N 14.08. Found:C 53.35; H 4.04; N 13.50.

EXAMPLE 66 In vivo activity

According to an in vivo systemic candidiasis model in mice described inEP 332,387 in which all the the animals of the control group died within3 days after inoculation, 90% to 100% of the animals treated with 20mg/kg p.o. at times 1, 4 and 24 h after inoculation with the products ofexamples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 19, 21, 23, 25,29, 32, 35, 38, 41, 44, 49, 50, 53, 54, 57 and 63 survived at the end ofthe study (day 10). Under these experimental conditions, the knowncompound fluconazole at 20 mg/kg showed a 80-90% protection.

We claim: a salt or solvate thereof.
 1. A compound of the formula##STR110## as a racemate, a diastereoisomer mixture or as a homochiralcompound wherein:X is CH or N; Ar represents phenyl or a phenyl ringsubstituted with one or more halogen and/or trifluoromethyl groups; Z is--C (=O)-- or --SO₂ --; B is O, in which case the dotted line representsa covalent bond, or B is hydroxy, fluorine, hydrogen or1-H-1,2,4-triazol-1-yl, in which case the dotted line is absent; R₄ isC₁₋₄ alkyl; R₅, and R₆, are independently hydrogen or C₁₋₄ alkyl; when Zis --C(=O)--, R₂ is phenyl, phenyl substituted with one or more groupsR₁₀, or naphthyl; when Z is --SO₂ --, R₂ is C₁₋₄ -alkyl, phenyl--C₁₋₄-alkyl, phenyl or phenyl substituted with one or more groups R₁₀ ; R₁₀represents C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxy, C₁ -C₄haloalkoxy, halogen, nitro, cyano, hydroxy, benzyloxy, hydroxymethyl, agroup of formula --CH₂ --OCO--(C₁₋₄ alkyl), a group of formula --CO--(C₁₋₄ alkyl), a group of formula --COO-- (C₁₋₄ alkyl), a group offormula --SO₂ (C₁₋₄ Alkyl) wherein z is 0, 1 or 2, amino, mono- ordialkylamino wherein alkyl means C₁ -C₄ alkyl; or a salt or solvatethereof.
 2. A compound according to claim 1 wherein:X is N; R₂ is phenylor phenyl substituted with one or more groups R₁₀ ; and Ar, Z, R₄, R₅,R₆ and R₁₀ have the previously defined meaning.
 3. A compound accordingto claim 1 wherein:X is N; Z is --C(=O)--; R₂ is phenyl or phenylsubstituted with one or more groups R₁₀ ; and Ar, R₄, R₅, R₆ and R₁₀have the previously defined meaning.
 4. A compound according to claims 2wherein:X is N; Z is --C(=O)--; R₂ is phenyl or phenyl substituted withone or more groups R₁₀ ; R₄ is methyl; R₅ is hydrogen or methyl; and Ar,R₆ and R₁₀ have the previously defined meaning.
 5. A compound accordingto claim 1 wherein:X is N; Z is --C(=O)--; R₂ is 4-chlorophenyl,4-fluorophenyl, 4-(trifluoromethyl)phenyl,2-fluoro-4-(trifluoromethyl)phenyl, 4-cyanophenyl, 4-nitrophenyl,4-(trifluoromethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl or4-(2,2,3,3-tetrafluoropropoxy)phenyl; R₄ is methyl; R₅ is hydrogen; Aris 4-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or 4-chlorophenyl; and R₆is hydrogen.
 6. A compound according to claim 1 wherein:X is N; Z is--C(-O)--; R₂ is 4-chlorophenyl, 4-fluorophenyl,4-(trifluoromethyl)phenyl, 2-fluoro-4-(trifluoromethyl)phenyl,4-cyanophenyl, 4-nitrophenyl, 4-(trifluoromethoxy)phenyl,4-(2,2,2-trifluoroethoxy)phenyl or 4-(2,2,3,3-tetrafluoropropoxy)phenyl;R₄ is methyl; R₅ is hydrogen; B is O in which case the dotted linerepresents a covalent bond, or B is hydroxy, in which case the dottedline is absent; Ar is 4-fluorophenyl, 2-cloro-4-fluorophenyl,2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or4-chlorophenyl; and R₆ is hydrogen.
 7. A compound according to claim 5wherein:X is N; Z is --C(=O)--; R₂ is 4-chlorophenyl, 4-fluorophenyl,4-(trifluoromethyl)phenyl, 2-fluoro-4-(trifluoromethyl)phenyl,4-(trifluoromethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl or4-(2,2,3,3-tetrafluoropropoxy)phenyl; R₄ is methyl; R₅ is hydrogen; Aris 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or4-chlorophenyl; and R₆ is hydrogen.
 8. A compound according to claim 6whereinX is N; Z is --C(=O)--; R₂ is 4-chlorophenyl, 4-fluorophenyl,4-(trifluoromethyl)phenyl, 2-fluoro-4-(trifluoromethyl)phenyl,4-(trifluoromethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl or4-(2,2,3,3-tetrafluoropropoxy)phenyl; R₄ is methyl; R₅ is hydrogen; B isO in which case the dotted line represents a covalent bond; Ar is2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or4-chlorophenyl; and R₆ is hydrogen.
 9. A compound according to claim 6wherein:X is N; Z is --C(=O)--; R₂ is 4-chlorophenyl, 4-fluorophenyl,4-(trifluoromethyl)phenyl, 2-fluoro-4-(trifluoromethyl)phenyl,4-(trifluoromethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl or4-(2,2,3,3-tetrafluoropropoxy)phenyl; R₄ is methyl; R₅ is hydrogen; B ishydroxy, in which case the dotted line is absent; Ar is2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or4-chlorophenyl; and R₆ is hydrogen.
 10. (SR*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-l,2,4-triazol-1-yl)methyl]-2-morpholinoneor a salt or solvate thereof. 11.(SR,6R)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinoneor a salt or solvate thereof. 12.(SR*,6R*)-6-[2,4-Dichlorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinoneor a salt or solvate thereof. 13.(5R,6R)-6-[2,4-Dichlorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinoneor a salt or solvate thereof. 14.(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-2-hydroxy-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholineor a salt or solvate thereof. 15.(SR,6R)-6-[2,4-Difluorophenyl]-5-methyl-2-hydroxy-4-[4-(trifluoromethyl)-benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholineor a salt or solvate thereof. 16.(5R*,6R*)-6-[2,4-Dichlorophenyl]-5-methyl-2-hydroxy-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholineor a salt or solvate thereof. 17.(SR,6R)-6-[2,4-Dichlorophenyl]-5-methyl-2-hydroxy-4-[4-(trifluoromethyl)-benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholineor a salt or solvate thereof. 18.(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-4-[2-fluoro-4-(trifluoromethyl)-benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]-2-morpholinoneor a salt or solvate thereof. 19.(5R,6R)-6-[2,4-Difluorophenyl]-5-methyl-4-[2-fluoro-4-(trifluoromethyl)-benzoyl]-6-[(1H-I,2,4-triazol-]-yl)methyl]-2-morpholinoneor a salt or solvate thereof. 20.(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholine,or a pharmaceutically acceptable salt or solvate thereof. 21.(5R,6R)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]6[(1H-1,2,4-triazol-1-yl)methyl]morpholine,or a pharmaceutically acceptable salt or solvate thereof. 22.(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl) methyl]morpholine ethanolate. 23.(5R,6R)-6-[2,4-Difluorophenyl]-5-methyl-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholine ethanolate. 24.(5R*,6R*)-6-[2,4-Difluorophenyl]-5-methyl-2-hydroxy-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl) methyl]morpholine ethanolate. 25.(5R,6R)-6-[2,4-Difluorophenyl]-5-methyl-2-hydroxy-4-[4-(trifluoromethyl)benzoyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]morpholineethanolate.
 26. A pharmaceutical composition which comprises aneffective amount of a compound as defined in claim 1 or apharmaceutically acceptable salt or solvate thereof in admixture with apharmaceutically acceptable excipient.
 27. A method for treating orpreventing fungal infections in an animal, which may be a human being,which comprises administering to an animal in need thereof an effectiveamount of a compound as defined in claim 1 or a pharmaceuticallyacceptable salt or solvate thereof.
 28. An agrochemical compositioncomprising an effective amount of a compound as defined in claim 1 or asalt or solvate thereof in admixture with an agronomically acceptableexcipient.
 29. A method of combatting fungal diseases in a plant whichcomprises administering to the plant an effective amount of a compoundas defined in claim 1 or a salt or solvate thereof.